Rna sequencing to diagnose sepsis and other diseases and conditions

ABSTRACT

Deep RNA sequencing is a technology that provides an initial diagnostic for sepsis that can also monitor the indicia of treatment and recovery (bacterial counts reduce, physiology returns to steady-state). The invention can be used for many other hospital conditions, particularly those needing an intensive care unit stay with the attendant risk of bacterial infection, such as trauma, stroke, myocardial infarction, or major surgery.

REFERENCE TO RELATED APPLICATIONS

This patent matter claims priority under 35 U.S.C. § 119(e), to U.S. Ser. No. 63/176,531, filed Apr. 19, 2021, and 63/184,583, filed May 5, 2021, the contents of both of which are incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under P20 GM103652, T32 HL134625, R35 GM142638, P20 GM121344 awarded by National Institutes of Health. The government has certain rights in the invention.

FIELD OF THE INVENTION

This invention generally relates to chemical analysis of biological material, using nucleic acid products used in the analysis of nucleic acids, e.g., primers or probes for diseases caused by alterations of genetic material.

BACKGROUND OF THE INVENTION

Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. Despite declining age-standardized incidence and mortality, sepsis remains a significant cause of health loss worldwide. Rudd et al., The Lancet, 395(10219), 200-211 (Jan. 18, 2020). Sepsis is treatable, and timely implementation of targeted interventions improves outcomes.

Sepsis is diagnosed clinically by the presence of acute infection and new organ dysfunction. Singer et al., JAMA, 315, 801-810 (February 2016). Unlike the previous concepts of septicemia or blood poisoning, the definition of sepsis extends across bacterial, fungal, viral, and parasitic pathogens. The definition focuses on the host response as the major source of morbidity and mortality. Bone et al., Chest, 101, 1644-1655 (1992). Globally, there were about 48.9 million cases of sepsis in 2017, with about 11.0 million total sepsis-related deaths worldwide, representing 19.7% (18·2-21·4). This number may be a substantial undercount. Rudd et al., The Lancet, 395(10219), 200-211 (Jan. 18, 2020). Sepsis results from an underlying infection, so sepsis is an intermediate cause of health loss. Because, according to the principles of the International Classification of Diseases (ICD), causes of death are assigned based on the underlying disorder that triggers the chain of events leading to death rather than intermediate causes, sepsis, when reported as the cause of death, are considered miscoded.

Thus, the global burden of sepsis is more significant than previously appreciated. There is substantial variation in sepsis incidence and mortality according to Healthcare Access and Quality Index (HAQ Index), Lancet, 390, 231-266 (2017)), with the highest burden in places that cannot prevent, identify, or treat sepsis. Further research is needed to understand these disparities and developing policies and practices targeting their amelioration. More robust infection-prevention measures should be assessed and implemented in areas with the highest incidence of sepsis and among populations on which sepsis has the most significant impact. The impact of sepsis is especially severe among children, so more than half of all sepsis cases worldwide in 2017 occurred among children, many neonates.

Physicians diagnose sepsis using clinical judgment under one or more clinical scores. The systemic inflammatory response syndrome (SIRS) approach assesses an inflammatory state affecting the whole body, which is the body's response to an infectious or non-infectious challenge. Jui et al. (American College of Emergency Physicians), Ch. 146: Septic Shock. in Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7th edition, (New York: McGraw-Hill, 2011). pp. 1003-14. Sepsis has both pro-inflammatory and anti-inflammatory components. The qSOFA approach simplifies the SOFA score by including only its three clinical criteria and by including any altered mentation. Singer et al., JAMA, 315, 801-810 (February 2016). qSOFA can easily and quickly be repeated serially on patients.

A culture of the bacterial infection confirms a diagnosis of sepsis. A culture diagnosis can be delayed by forty-eight hours and sometimes cannot be performed successfully. Clinical judgment sometimes misses sepsis.

Biomarkers are being developed for sepsis, but no reliable biomarkers exist. A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. Still, the level alone could not definitively make the diagnosis. Wacker et al., The Lancet Infectious Diseases. 13(5), 426-35 (May 2013). A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. Backes et al. Intensive Care Medicine, 38(9): 1418-28 (September 2012).

There remains a need in the medical art for a better diagnosis of sepsis.

SUMMARY OF THE INVENTION

The concept of diagnostics is analogous to using a fishing lure to find a single protein, gene, or RNA sequence. The invention provides an improved concept, using a fishing net to obtain all the RNA data in a sample, and use computational biology to better sort through all the data (fish) to identify patients with sepsis and the bacteria causing the immune response. The invention provides an initial diagnostic for sepsis that can also monitor the indicia of treatment and recovery (bacterial counts reduce, physiology returns to steady-state). The invention can be used for many other hospital conditions, particularly those needing an intensive care unit stay with the attendant risk of bacterial infection, such as trauma, stroke, myocardial infarction, or major surgery.

In the first embodiment, the invention provides unmapped bacterial RNA reads to identify bacteria that cause sepsis. In the second embodiment, the invention provides unmapped viral reads to identify sepsis or viral reactivation. In the third embodiment, the invention provides the use of unmapped B/T V(D)J to identify sepsis. In the fourth embodiment, the invention provides Principal Component Analysis of RNA splicing entropy to identify sepsis. In the fifth embodiment, the invention provides RNA lariats to identify sepsis. In the sixth embodiment, the invention provides a Principal Component Analysis of gene expression, alternative RNA splicing, or alternative transcription start and end to identify sepsis.

In producing the listed embodiments, one of ordinary skill in the molecular biological art uses one or more of these steps.

The first step is for one of ordinary skill in the molecular biological art to obtain RNA sequencing from a body sample. In the seventh embodiment, the body sample is a bodily fluid sample. In the eighth embodiment, the bodily fluid sample is blood. In the ninth embodiment, the target is 100,000,000 reads/sample.

The second step is for one to align the RNA sequencing data (reads) to the genome of interest. In the tenth embodiment, the reads from a human sample are aligned to a human genome. In the eleventh embodiment, the reads from a mouse sample are aligned to a mouse genome.

The third step is to select the un-mapped reads and analyze the reads using a Read Origin Protocol (ROP).

In the first embodiment, the next step is to identify bacteria present in the sample. From the ROP, one of ordinary skill in the molecular biological art identifies bacteria present in the sample. In the twelfth embodiment, one of ordinary skill in the molecular biological art or medical art uses the identified bacteria to list potential causative organisms of sepsis (product).

In the second embodiment, from the ROP, the next step is to identify the viruses present in the sample. In the thirteenth embodiment, one uses the virus identified with PCA to identify likely sepsis samples.

In the third embodiment, from the ROP, the next step is to identify the T/B cell epitopes present in the samples. In the fourteenth embodiment, one uses the T/B cell epitopes identified with PCA to identify likely sepsis samples.

Alternatively, or in combination, in the third step, one selects the mapped reads and then uses a program that enables detection and quantification of alternative RNA splicing events to identity gene expression, RNA splicing events, alternative transcription start/end, or RNA splicing entropy. In a fifteenth embodiment, the program that enables detection and quantification of alternative RNA splicing events is Whippet. In the sixteenth embodiment, one uses the gene expression changes, RNA splicing events, and alternative transcription start/end with PCA to identify likely sepsis samples. In the seventeenth embodiment, one uses the RNA splicing entropy identified with PCA to identify likely sepsis samples.

In the fifth embodiment, from the gene expression, RNA splicing events, alternative transcription start/end, or RNA splicing entropy, the next step is for one to identify RNA lariats from the mapped reads. In the eighteenth embodiment, one uses the RNA lariats with PCA to identify likely sepsis samples.

In the nineteenth embodiment, the invention provides an output product with five plots comprising bacterial RNA reads, viral reads, B/T V(D)J epitopes, RNA splicing entropy, and RNA lariat embodiments described above and a list of likely bacteria causing the infection.

RNA sequencing data be used in several ways. (1) Identification of biomarkers. Rather than need to pick a subset to test for, RNA sequencing data can identify genes with increased expression that would correlate to biomarkers of interest. (2) Identification of new biomarkers. RNA sequencing data allows for analysis of processes such as RNA splicing. The method of RNA splicing entropy can be quantified and grouped according to a Principal Component Analysis into sick or not sick. RNA lariats can also be identified in sequencing data and used as a potential biomarker. All biomarkers can be followed over time to assess for resolution of the sepsis. (3) Use of un-mapped reads in sepsis. RNA sequencing typically aligns with the genome of reference (i.e., the human genome). Reads that are not aligned to the human genome are discarded (the percentage of un-mapped reads could itself be a biomarker). These un-mapped reads could be of two major potential interests. (4) Identification of the microbe causing the infection. The unmapped reads can be referenced to the genome of disease-causing microbes (bacteria, viruses, fungi, etc.) to identify the causative organism and start treatment earlier. Serial measurements can also assess the effectiveness of treatment.

The results presented show that mice exposed to trauma separated from controls using PCA. Similarly, mice that did not survive fourteen days post exposure clustered closely together on PCA. These results show a substantial difference in global pre-mRNA processing entropy in mice exposed to trauma vs. controls, and that pre-mRNA processing entropy is useful in predicting mortality.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart showing Principal Component Analysis of samples in the blood. Three mice exposed to the trauma model were compared to three mice in the control group (total n=6). When plotting the first two principal components against each other, the exposed mice separated from the control mice. Samples clustered based on tissue type and ARDS status on the Principal Component Analysis plot, suggesting that splicing entropy can be a biomarker for ARDS status. The first two principal components plotted against each other. The percentages in parentheses represent the percent variability explained by the principal component. Circles represent control mice; squares represent mice exposed to hemorrhage followed by cecal ligation and puncture.

FIG. 2 is a chart showing a Principal Component Analysis of the survival study. Ten mice exposed to trauma were part of the survival experiment. A mortality rate of 30% was observed, which is consistent with previous studies using this model. When plotting the first two principal components against each other, the mice who did not survive closely clustered together. The first two principal components are plotted against each other. The percentages represent the percent variability explained by the principal component. The squares represent mice that died by fourteen days post CLP, circles represent mice that survived.

FIG. 3 confirms by real time PCR that the peak SARS-CoV-2 RNA described in this specification is higher than the rest of the N-gene in the blood of critically ill COVID-19 patients.

FIG. 4 is a pair of figures showing the SARS-CoV-2 reads per patient. The top panel is a bar graph showing the number of reads aligning to the SARS-CoV-2 genome from each patient. Most reads aligned to loci encoding the N protein (red bar) or the RNA dependent RNA polymerase (black bar). Bottom panel is the location where the cumulative reads from all the patients align to the SARS-CoV-2 genome. Genes encoding the RNA dependent RNA polymerase and the N protein are at positions ˜15,000 and ˜29,000, respectively.

FIG. 5 is a graph created by the principal component analysis of the >380,000 entropy values related to alternative RNA splicing and alternative transcription start/end. Patients labeled in red died from COVID-19 and surviving patients are labeled with green dots. Mortality rate above PC2=0 is 75% and below is 14% (p=0.04)

FIG. 6 (TABLE 1) is a list of the clinical and demographic data for fifteen study participants.

FIG. 7 (TABLE 2) is a list of the counts per patient from Kraken2 assays performed for the fifteen study participants.

FIG. 8 (TABLE 3) is a list of the gene difference between patients that died versus patients that lived among the fifteen study participants.

DETAILED DESCRIPTION OF THE INVENTION Industrial Applicability

Despite causing death in one out of five people in the world, there is not a single standard test to diagnose sepsis. Despite declining age-standardized incidence and mortality, sepsis remains a significant cause of health loss worldwide. Rudd et al., The Lancet, 395(10219), 200-211 (Jan. 18, 2020). Sepsis patients undergo the physiology common to patients in the intensive care unit: hypotension, tachycardia, hyperthermia, and hypoxia.

Delays in treatment for sepsis impact mortality. Early identification of the differences between clinically similar patients would allow for earlier interventions (surgery, antibiotics). Using RNA sequencing technology combined with computation biology techniques to understand RNA biology the differences in these two patients could be identified. Earlier prediction of complications would also allow for triage of patients to facilities equipped to deal with them and allow for better discussions regarding expected mortality and morbidity.

It takes days to get a final diagnosis for bacterial pathogen, since culturing of the bacteria is needed. Confirming bacteremia is done microbial blood culture, but the turnaround time can lead to a delay in diagnosis. Biron et al., Biomarker Insights. 10(Suppl 4), 7-17 (Sep. 15, 2015). Procalcitonin (PCT) has been shown to correlate more closely to onset and treatment of sepsis than C-reactive protein (CRP). Vijayan et al., J. Intensive Care (Aug. 3, 2017). Much work has been done with PCT as a predictor of sepsis before symptom onset. Dolin et al., Shock, 49(4), 364-70 (April 2018). PCT has low specificity for sepsis, and is elevated in cancers, autoimmune diseases, and other physiological stressors. Bloos & Reinhart, Virulence, 5(1), 154-60 (Jan. 1, 2014).

RNA sequencing data can identify the bacteria more quickly than culture. The drop in the cost of sequencing has refocused genetic analyses from DNA to RNA sequencing. Methods to analyze this data have improved. Stark et al., Nature Reviews Genetics (2019). Compared to DNA. RNA undergoes dynamic changes by transcription and post-transcriptional processing, providing unique insight into cellular activity. RNA reflects a broader source of infectious etiologies, given that both DNA and RNA viruses have RNA genetic material, whether in the genome or by transcription of mRNA. Patients with trauma who die or have complications are expected to have different changes in expression, alternative RNA splicing, and alternative transcription start/end compared to patients who survive and do not have a complication. The differences seen in RNA biology may correlate with injury severity or predict outcomes. This invention should help direct care in trauma patients when RNA sequencing speeds increase to allow for results that are available when needed for patients in the ICU (within one hour).

RNA sequencing data related to other processes (RNA splicing entropy, gene expression, viral counts, lariat counts, etc.) provide a signature that can identify patients with sepsis. A better understanding of RNA biology in the clinical scenario of critically ill sepsis patients can have a broad impact on biomedical science. When the information in RNA sequencing data can identify patients who have not resolved the immune response to the initial sepsis, outcomes can improve.

The number of unmapped reads aligning to viral pathogenic genomes can be a biomarker of critical illness. Patients with late death should have different gene expression, alternative RNA splicing (including RNA splicing entropy), and alternative transcription start/end as compared to patients with an early death. the genes with increased alternative RNA splicing (including RNA splicing entropy), and alternative transcription start/end are expected to be different in the patients who died late compared to those who died early. These identified genes provide insight into proteins not considered in trauma patients as potential biomarkers or targets of therapeutic intervention but point to pathological mechanism not appreciated or unclear.

RNA biology before the trauma should be able to predict survivors. Mice that survive to fourteen days should have less RNA biology changes compared to mice at the early time point. This are done across three distinct background mice to account for the heterogeneity of humans and the comparability of the two most common immunological/genetic mouse model strains used. As it relates to comparing samples across mouse strains, since gene expression. RNA splicing, and alternative transcription start/end are all basic molecular functions, the results remain similar across the multiple strains.

Identification of B and T cell epitopes from the unmapped reads could be a biomarker for sepsis. Critical illness decreases the diversity of these epitopes. A resolution could signal an improvement in clinical status. Losing some epitopes could indicate immune suppression seen in critical illness.

Alternative transcription starts and end is another biological process potentially influenced by sepsis. Current technology now allows us to identify changes in transcription with RNA sequencing data. Hardwick et al., Frontiers in Genetics. 10, 709 (2019); Cass & Xiao X, Cell Systems, 9(4), 23, 393-400.e6 (October 2019). The genes that have increased difference in alternative transcription start/end could be disease treatment targets. A change to the start or end of the RNA is likely to change the ultimate endpoint of that transcript. Understanding the changes in transcription start and end would better describe the ultimate result of proteins since that were thought to be transcribed and translated could have been transcribed (with changes in the start or end) which led to nonsense mediated decay or the translation of an alternative isoform.

Genes with significant alternative splicing and high entropy in the mouse after trauma may be target for intervention. This invention can better diagnose sepsis and the microbe causing the disease. Emergency room and critical care physicians can use the invention.

Solution: RNAs as Biomarkers of Critical Illness

While proteins have traditionally been used to reflect inflammatory load, RNAs are more specific to certain etiologies and clinical outcomes.

High through-put sequencing technologies allows for coding and non-coding RNAs (ncRNA) as markers of disease risk and progression. Next-generation sequencing (NGS) quantifies RNAs by sequencing of complementary DNA (cDNA), allowing transcriptomic analysis of mRNAs, ribosomal RNAs (rRNA), and ncRNAs. Kukurba & Montgomery, Cold Spring Harb. Protoc., 2015(11), 951-69 (Apr. 13, 2015).

Coding and non-coding RNAs have been studied as biomarkers. Less attention has been on the portion of data produced (9-20%) via RNA-sequencing that is consistently discarded when it cannot be mapped to a reference genome. Mangul et al., ROP: Dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol., 19 (Feb. 15, 2018).

The discovery of serum-stable circulating miRNAs allows the use of cell-free miRNAs as biomarkers of disease. Benz et al., Int. J. Mol. Sci., 17(1) (Jan. 9, 2016); Wang et al., J. Cell Physiol., 231(1), 25-30 (2016). Elevated miR-133a levels in serum correlate to poorer prognosis in ICU patients. Tacke et al., Crit. Care Med., 42(5), 1096-104 (May 2014). Groups of miRNAs delineate between different infectious etiologies, such as S. aureus and E. coli. Wu et al., PLoS One, 8(10) (2013). The lack of standardization in measuring circulating miRNA expression affects reproducibility between analyses and limited its clinical applicability. Lee et al., Mol. Diagn. Ther., 21(3), 259-68 (June 2017).

Physiologic stress induces viral reactivation by impairing the immune response and upregulating cell cycle progression pathways such as MAPK and NF-κB. Walton et al., PLoS One, 9(6), e98819 (Jun. 11, 2014); Traylen et al., Future Virol., 6(4), 451-63 (April 2011). Secretion of pro-inflammatory cytokines, such as TNF-α, functions in reactivating latent cytomegalovirus (CMV) in patients that had undergone recent stress even absent systemic inflammation. Prösch et al., Virology, 272(2), 357-65 (Jul. 5, 2000). A combination of inflammatory challenges and immune cell dysregulation has been shown to contribute to an environment that both promotes viral reactivation and maintains viremia. Walton et al., PLoS One, 9(6), e98819 (Jun. 11, 2014).

In a traumatic shock EXAMPLE, C57BL6 mice were treated by sequential hemorrhagic shock followed by cecal ligation and puncture, which induces sepsis. RNA was extracted from cellular component of lung and immune cells in blood after discarding plasma and serum. Samples were collected from both healthy and critically ill mice and sequenced via NGS at Gene Wiz in South Plainfield, N.J., USA. Reads were aligned to mm9 genome using STAR and then unmapped reads were mapped to viral genomes via ROP. Dobin et al., Bioinformatics, 29(1), 15-21 (January 2013). Mangul et al., Genome Biol., 19 (Feb. 15, 2018). Two-sample t tests were conducted to compare number of viral reads in healthy versus critically ill mouse lung and blood.

Definitions

For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are listed below. Unless stated otherwise or implicit from context, these terms and phrases have the meanings below. These definitions are to aid in describing particular embodiments and are not intended to limit the claimed invention. Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For any apparent discrepancy between the meaning of a term in the art and a definition provided in this specification, the meaning provided in this specification shall prevail.

Acute respiratory distress syndrome (ARDS) has the medical art-defined meaning. ARDS is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath, rapid breathing, and bluish skin coloration. Causes may include sepsis, pancreatitis, trauma, pneumonia, and aspiration.

Alternative splicing (AS) has the molecular biological art-defined meaning. RNA splicing is a basic molecular function that occurs in all cells directly after RNA transcription, but before protein translation, in which introns are removed and exons are joined. Alternative splicing or alternative RNA splicing, or differential splicing, is a regulated process during gene expression that results in a single gene coding for multiple proteins. Exons of a gene can be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. The proteins translated from alternatively spliced mRNAs can contain differences in their amino acid sequence and, often, in their biological functions.

Aldo/keto reductase gene has the molecular biological art-defined meaning.

Base R is an R-based computer program.

Mann Whitney U tests has the statistical art-defined meaning. The Mann-Whitney U test (also called the Mann-Whitney-Wilcoxon (MWW), Wilcoxon rank-sum test, or Wilcoxon-Mann-Whitney test) is a nonparametric test of the null hypothesis that it is equally likely that a randomly selected value from one population is less than or greater than a randomly selected value from a second population. This test Can investigate whether two independent samples were selected from populations having the same distribution.

mountainClimber is a cumulative-sum-based approach to identify alternative transcription start (ATS) and alternative polyadenylation (APA) as change points. Unlike many existing methods, mountainClimber runs on a single sample and identifies multiple ATS or APA sites anywhere in the transcript. Cass & Xiao, Cell Systems, 9(4), 23, 393-400.e6 (October 2019).

Next Generation Sequencing (NGS) has the molecular biological art-defined meaning. NGS technology is typically characterized by being highly scalable, allowing the entire genome to be sequenced at once. Usually, this is accomplished by fragmenting the genome into small pieces, randomly sampling for a fragment, and sequencing it using one of a variety of technologies.

Principal Component Analysis (PCA) has the computer-art and molecular biological art-defined meaning. Principal component analysis is a statistical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables (entities each of which takes on various numerical values) into a set of values of linearly uncorrelated variables called principal components.

Read origin protocol (ROP) has the computer-art meaning of is a computational protocol that aims to discover the source of all reads, including those originating from repeat sequences, recombinant B and T cell receptors, and microbial communities. The Read Origin Protocol was developed to determine what the unmapped reads represented. Mangul al., Genome Biology 19, 36 (2018). Recent development of Read Origin Protocol (ROP) has demonstrated that unmapped reads align to bacterial, viral, fungal, and B/T rearrangement genomes.

Read has the molecular biological art-defined meaning of reading sequencing results to determine nucleotide base structure.

Sepsis has the medical art-defined meaning of a life-threatening condition that arises when the body's response to infection injures its tissues and organs. Bone et al., Chest, 101, 1644-1655 (1992); Singer et al., JAMA, 315, 801-810 (February 2016).

STAR aligner is the Spliced Transcripts Alignment to a Reference (STAR), a fast RNA-seq read mapper, with support for splice-junction and fusion read detection. STAR aligns reads by finding the Maximal Mappable Prefix (MMP) hits between reads (or read pairs) and the genome, using a Suffix Array index. Different parts of a read can be mapped to different genomic positions, corresponding to splicing or RNA-fusions. The genome index includes known splice-junctions from annotated gene models, allowing for sensitive detection of spliced reads. STAR performs local alignment, automatically soft clipping ends of reads with high mismatches. Dobin et al., STAR: Ultrafast universal RNA-seq aligner. Bioinformatics, 29(1), 15-21 (January 2013).

Treatment for sepsis has the medical-art recognized meaning. Sepsis is treatable, and timely implementation of targeted interventions improves outcomes. The Mayo Clinic informs the public that several medications are used in treating sepsis and septic shock. They include antibiotics. Broad-spectrum antibiotics, which are effective against a variety of bacteria, are usually used first. After learning the results of blood tests, a doctor may switch to a different antibiotic that's targeted to fight the specific bacteria causing the infection. They include intravenous fluids and vasopressors. Other medications include low doses of corticosteroids, insulin to help maintain stable blood sugar levels, drugs that modify the immune system responses, and painkillers or sedatives.

Treatment for COVID-19 has the medical-art recognized meaning. Corticosteroids can be therapeutic. See Prescott & Rice, Corticosteroids in COVID-19 ARDS: Evidence and hope during the pandemic. JAMA, 324, 1292-1295 (2020). Other treatments are known by persons having ordinary skill in the medical art. See Waterer & Rello, Steroids and COVID-19: We need a precision approach, not one size fits all. Infectious Diseases and Therapy (2020). See also Beigel et al., Remdesivir for the treatment of Covid-19—Preliminary Report. New England Journal of Medicine (2020).

Treatment for Acute respiratory distress syndrome (ARDS) has the medical-art recognized meaning. Corticosteroids can be therapeutic. See Prescott & Rice, Corticosteroids in COVID-19 ARDS: Evidence and hope during the pandemic. JAMA, 324, 1292-1295 (2020). Other treatments are known by persons having ordinary skill in the medical art.

V(D)J recombination has the molecular biological art-defined meaning. V(D)J recombination occurs in developing lymphocytes during the early stages of T and B cell maturation, involves somatic recombination, and results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively.

Whippet (OMICS_29617) is a program that enables detection and quantification of alternative RNA splicing events of any complexity with computational requirements compatible with a laptop computer. Whippet applies the concept of lightweight algorithms to event-level splicing quantification by RNAseq. The software can facilitate the analysis of simple to complex AS events that function in normal and disease physiology. Alternative splicing events with high entropy are identified using Whippet. Sterne-Weiler et al., Molecular Cell, 72, 187-200.e186 (2018).

Materials and Methods

Mouse strains. Mice are purchased from The Jackson Laboratory. C57BL/6J, the most popular mouse model used, exhibits a Th1/more pro-inflammatory phenotype. C57BL/6J is also the background of numerous knock out animals. BALB/cJ is also another commonly used mouse and can be the background of analyses with knockout animals but has more of a Th1/anti-inflammatory predominant repose phenotype. The CAST mouse is derived from wild mouse and genetically different from common laboratory mice. Using these three strains adjusts for the heterogeneity seen in humans.

Mouse model of sepsis: cecal ligation and puncture (CLP). A mouse model of hemorrhagic shock followed by the induction of sepsis by cecal ligation and puncture induces severe sepsis. Lomas-Neira et al., Shock, 45(2), 157-65 (2016)); Monaghan et al., Mol Med., 24(1), 32 (Jun. 18, 2018); Wu et al., PLoS One, 8(10) (2013); Monaghan et al., Annals of Surgery, 255, 158-164 (2012). Anesthetized, restrained mice in supine position catheters are inserted into both femoral arteries. Mice are bled over a 5-10-minute period to a mean blood pressure of 30 mmHg (±5 mmHg) and kept stable for 90 minutes. To achieve this level of hypotension, the mice have one mL of blood withdrawn. One mL of blood is approximately 50% of their blood volume so this correlates to class 4 hemorrhagic shock in humans. Mice are resuscitated intravenously (IV) with Ringers lactate at four times drawn blood volume. Sham hemorrhages are performed as a control in which femoral arteries ligated, but no blood is drawn to mimic the tissue destruction. The following day, sepsis is induced as a secondary challenge by cecal ligation and puncture. The timing of this secondary challenged is based on previous findings that hemorrhagic shock followed twenty-four hours by the induction of sepsis produced results in line with critical illness such as altering PaO₂ to FIO₂ ratios. The mouse model uses a double hit of hemorrhagic shock followed by cecal ligation and puncture correlates to a missed bowel injury in humans after hemorrhagic shock. This mouse model correlates with an injury severity score (ISS) of twenty-five. The dual challenge of hemorrhagic shock followed by septic shock is in line with the sepsis patients who are critically ill. Sometimes patients present with bleeding from wounds and a bowel injury missed upon initial assessment.

Sample sizes for these assays are based upon results from the inventor's previous work looking at the alternative splicing of sPD-1 and an effect size of Cohen's d=2.85 standard deviations difference between groups was calculated. With such a large effect size, power analysis poorly justifies sample size since, if the effect size is tenable, it would be exceedingly rare for assays of any sample size to fail to reach statistical significance. Small sample sizes provide poor point estimates and may be very unstable. the inventors chose a sample size of six mice per group based on feasibility and hoping to provide a reasonable point estimate for each group.

Mice of both sexes are used, because there are significant sex differences in the response to bleeding from trauma. Deitch et al., Annals of Surgery, 246(3), 447-53; discussion 53-5 (2007).

Human subjects. Patients are recruited from the Trauma Intensive Care Unit (TICU) at Rhode Island Hospital with Institutional Review Board approval and consent. The patient population at Rhode Island Hospital (a level 1 trauma center) is sufficient for this EXAMPLE. Over 3700 trauma patients were admitted to the hospital in 2018. The TICU admitted 765 patients in 2018. This would cause over 3000 patients admitted to the intensive care unit over the 4-year project. Using the advanced technology of the hospital's electronic health records (EPIC) combined with the mandated trauma registry there are streamlined efforts to recruit and retain patients. Since the mouse model correlates to an injury severity score (ISS) of twenty-five, the goal is to ensure that the average ISS for all the patients is twenty-five. Minimal risk to the patient is maintained since there is no direct benefit; the blood collected are less than 50 mL over an 8-week period and not collected more than twice a week. Blood samples from patients are taken on admission (25 mL) and during the TICU stay when a complication is developed (25 mL). This should cause the maximum for the initial 8-week period after the trauma. When the patient is recovered, at least 8 weeks after the last blood draw, a final blood draw 50 mL of are done in the outpatient setting. A power analysis was done based upon previous results from human patients. The effect size of Cohen's d=0.8 using a power of 80% and alpha of 0.05 the inventors calculated a sample size of twenty-six per group. The mortality of patients in the TICU is 5%. To enroll twenty-six patients who die after trauma, the inventors need 520 TICU patients (26/0.05=520). No enrollment is planned in the last six months to ensure adequate follow up, data collection and analysis. Fourteen % of patients in the TICU have complications after trauma. Due to the correlation to the mouse model of an ISS of twenty-five, the average ISS for the enrolled patients is targeted at twenty-five. This system recruits some patients who are not used. These patient samples are banked and not sent for RNA sequencing. After twenty-six patients who die and twenty-six patients with a complication are enrolled. The entire set of patients has an average ISS of twenty-five then recruitment conclude.

Where patients are being recruited, variables such as age, weight, and medical co-morbidities are collected and compared across groups. If these variables are different (t test or rank sum), these factors are adjusted for in the analysis by regression.

In the human studies, both sexes are recruited and analyzed in the GTEx data set. Age, weight, and other health problems are constant in the mouse assays.

Sample collection and sequencing. Mouse blood and lung samples were obtained as described. Monaghan et al., Annals of Surgery, 255, 158-164 (2012). Data for humans was obtained from GTEx by their protocols. RNA was extracted using the MasterPure Complete DNA/RNA Purification kit (epicenter, Madison Wis., USA) followed by the Globin Clear Kit (ThermoScientific, Waltham, Mass., USA). RNA was then sent to Genewiz (South Plainfield, N.J., USA) for sequencing as 1400 ng RNA in forty μL of fluid.

The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS and the data used for the analyses were obtained from the GTEx Portal and dbGaP accession number phs000424.v6.p1.

Cloud based computing. All computational biology work is performed on cloud-based computing by Lifespan-RI Hospital approved and supported Microsoft Azure environment. This server manages all large data sets from RNA sequencing. An intentional decision was made to use cloud-based computing for this project. Due to the depth of sequencing that is needed for RNA splicing analysis (100 million reads vs. forty million), more data is generated from both sequencing and analysis (a small study generated one terabyte of sequencing data and another terabyte from the alignment to the genome). With such a large amount of data predicted available for the EXAMPLE, the ability to expand and contract the storage space and computing power in the cloud is the ideal choice. This server stores and analyzes data from both mouse and human samples. Since RNA sequencing data is always identifiable, the data from humans are treated as though it is protected health information (PHI), even though none of the typical identifiers (such as name, date of birth, etc.) are associated with the data. The server was created in collaboration with the Information Technology department at Rhode Island Hospital to ensure data security. The cloud server is only accessible through a hospital virtual desktop and data are saved only to the Azure server or a hospital computer. Data are encrypted while stored, and when in transit to or from the hospital. Any link to typical identifiers (name, date of birth, etc.) are kept separate from the sequencing data. The cloud-based server allows for large data analysis with computing and storage needs changing on a per-use basis. The Azure server is Linux based and uses programming in R and Python. The following pipeline encompasses the typical analysis: differential expression, RNA analysis is done with Whippet. This also includes an entropy measure, and genes of interest undergo GO term analysis. Genes with alternative transcription start and end sites identified through Whippet are correlated with findings from the mountainClimber analysis.

Computational analysis and statistics. RNA sequencing data from the mouse was first checked for quality using FASTQC. RNA-sequencing data collected from the GTEx consortium, and the mouse ARDS model was analyzed with the Whippet software for differential gene processing. Alternative transcription events are those events identified by Whippet as ‘tandem transcription start site,’ ‘tandem alternative polyadenylation site,’ ‘alternative first exon,’ and ‘alternative last exon.’ Alternative RNA splicing events are those events labeled ‘core exon.’ ‘alternative acceptor splice site,’ ‘alternative donor splice site,’ and ‘retained intron.’ Alternative mRNA processing events were determined by a log 2 fold change of greater than 1.5+/−0.2. Statistical significance was calculated by the chi-square p-value of a contingency table based on 1000 simulations of the probability of each result.

Gene ontology (GO) was assessed using The Gene Ontology Resource Knowledgebase. Ashburner et al., Nature Genetics, 25, 25-29 (2000); The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Research, 47. D330-d338 (2019). Genes from the analyses were entered and outputs displayed. Outputs from gene ontology do not correlate with actual increase or decrease in a gene's expression but are related to expected based upon the set of genes entered.

Blood sample collection. Blood samples are collected on day 0 of ICU admission. Clinical data including COVID specific therapies was collected prospectively from the electronic medical record and participants were followed until hospital discharge or death. Ordinal scale can be collected as described by Beigel et al., New England Journal of Medicine (2020); along with sepsis and associated SOFA score, and the diagnosis of ARDS. See Singer et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315: 801-810 (2016); Ferguson et al. The Berlin definition of ARDS. Intensive Care Medicine, 38: 1573-1582 (2012).

RNA extraction and sequencing. Whole blood can be collected in PAXgene tubes (Qiagen, Germantown, Md.) and sent to Genewiz (South Plainfield, N.J., USA) for RNA extraction, ribosomal RNA depletion and sequencing. Sequencing can be done on Illumina HiSeq machines to provide 150 base pair, paired-end reads. Libraries were prepared to have three samples per lane. Each lane provided 350 million reads ensuring each sample had >100 million reads.

Computational Biology and Statistical Analysis. All computational analysis can be done blinded to the clinical data. The data can be assessed for quality control using FastQC. Andrews. A quality control tool for high throughput sequence data. FastQC (2014). RNA sequencing data can be aligned to the human genome utilizing the STAR aligner. Dobin et al., Bioinformatics (Oxford, England), 29, 15-21 (2013). Reads that aligned to the human genome can be separated and called ‘mapped’ reads. Reads that do not align to the human genome, which are typically discarded during standard RNA sequencing analysis, were identified as ‘unmapped’ reads. The unmapped reads then align to the relevant comparator and counted per sample using Magic-BLAST. See Boratyn et al., BMC Bioinformatics, 20, 405 (2019). The unmapped reads were further analyzed with Kraken2. See Wood, Lu, & Langmead, Genome Biology, 20, 257 (2019). The analysis used the PlusPFP index to identify other bacterial, fungal, archaeal, and viral pathogens. See Kraken 2/Bracken Refseq indexes maintained by BenLangmead, which uses Kutay B. Sezginel's modified version of the minimal GitHub pages theme.

Reads that align to the human genome, the mapped reads, also can undergo analysis for gene expression, alternative RNA splicing, and alternative transcription start/end by Whippet. See Sterne-Weiler et al., Molecular Cell, 72, 187-200.e186 (2018). When comparisons are made between groups (died vs. survived) differential gene expression can be set with thresholds of both p<0.05 and +/−1.5 log 2 fold change. Alternative splicing was defined as core exon, alternative acceptor splice site, alternative donor splice site, retained intron, alternative first exon and alternative last exon. Alternative transcription start/end events can be defined as tandem transcription start site and tandem alternative polyadenylation site. Alternative RNA splicing and alternative transcription start/end events can be compared between groups. See Sterne-Weiler et al., Molecular Cell, 72, 187-200.e186 (2018). Significance was set at great than 2 log 2 fold change as described by Fredericks et al., Intensive Care Medicine (2020). Genes identified from the analysis of mapped reads can be evaluated by GO enrichment analysis (PANTHER Overrepresentation released 20200728). See Mi et al. Nature Protocols, 8, 1551-1566 (2013).

Whippet can generate an entropy value for every identified alternative splicing and transcription event of each gene. These entropy values are created with no groups used in the gene expression analysis. To visualize this data a principal component analysis (PCA) can be conducted to reduce the dimensionality of the dataset and to obtain an unsupervised overview of trends in entropy values among the samples. Raw entropy values from all samples can be concatenated into one matrix and missing values were replaced with column means. Mortality can be overlaid onto the PCA plot to assess the ability of these raw entropy values to predict this outcome in this sample set. This analysis was done in R (version 3.6.3).

Kraken 2. The following tools are compatible with both Kraken 1 and Kraken 2. Both tools assist users in analyzing and visualizing Kraken results. Bracken allows users to estimate relative abundances within a specific sample from Kraken 2 classification results. Bracken uses a Bayesian model to estimate abundance at any standard taxonomy level, including species/genus-level abundance. Pavian has also been developed as a comprehensive visualization program that can compare Kraken 2 classifications across multiple samples. KrakenTools is a suite of scripts to help analyze Kraken results. For more information, a person having ordinary skill in the biomedical art can refer to Wood, Lu, & Langmead, Improved metagenomic analysis with Kraken 2, Genome Biology (Nov. 28, 2019).

The following EXAMPLES are provided to illustrate the invention and should not be considered to limit its scope.

Example 1 Unmapped Bacterial Reads to Identify Bacteria Causing Sepsis

Because bacterial infections are a common cause of morbidity in trauma patients, unmapped reads that align with bacteria are useful for the diagnosis and treatment of trauma patients. Unmapped reads from RNA sequencing data provide a valuable tool for the trauma patient. The decrease in the number of bacterial reads in the blood may be due to increased immune response. Some bacteria keep constant levels between groups, which signifies a virulent pathogen.

The technique of RNA sequencing has resulted in creating massive amounts of data. The first step with public RNA sequencing data is usually to align the reads to the reference genome of interest. RNA sequences that do not align with the reference genome (10-30%) are usually discarded when they cannot be mapped.

The inventors used a mouse model of hemorrhagic shock followed by cecal ligation and puncture. The inventors isolate RNA from blood and lung samples and had the RNA sequenced using standard techniques. They compare RNA from the test mice to sham controls. They analyze the RNA data that did not map to the mouse genome. Unmapped reads aligned to common bacterial pathogens, including Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. The inventors also identify specific genes with high read counts.

In one assay, the blood samples from the test mice exposed to trauma had fewer reads mapping to bacteria (365,974) as compared to the control mice (902,063, p=0.02). In the lung, the bacteria counts were similar. Despite an overall decrease in mapped bacterial RNA reads in the test mice, the three Streptococcus species and Staphylococcus aureus had a similar number of reads mapping between the test mice and the control mice. The most common RNA read mapped to aldo/keto reductase gene from group B strep (82793634[uid]). There was more expression of this gene in the blood of mice after trauma (15,096) compared to controls (3671, p=0.006). This difference was not seen in the lung compartment (13,691 vs. 15,996, p=0.24). In the blood of the test mice, most of the identified bacterial sequences were reduced in counts compared to the blood of the control mice (43 vs. 16).

Example 2 Unmapped Viral Reads to Identify Sepsis or Viral Reactivation

Unmapped data have been aligned to regions in the genomes of viruses. In critical illness, not only does the percentage of unmapped reads suggest a biomarker, but also the alignment of unmapped reads to some viral genomes. The percentage of unmapped reads in these organs during periods of critical illness can be a biomarker of severity and outcomes.

To assess the impact of critical illness on unmapped reads and their composition, the inventors expose mice (e.g., C57BL6 mice) to sequential treatment of hemorrhagic shock followed by sepsis. This treatment produces indirect acute respiratory distress syndrome (ARDS). RNA is extracted from lung and blood samples and sequenced via next-generation RNA-sequencing. Reads are aligned to the mm9 reference genome. The sources of unmapped reads were aligned by Read Origin Protocol (ROP). Changes in the viral signature of the unmapped reads are different when comparing blood to the lung.

In a second assay, the blood samples of critically ill mice averaged 31.9 million reads versus 32.1 million reads in healthy mice, and lung samples of critically ill mice averaged 33 million reads versus 33.7 million reads in healthy mice. The blood of critically ill mice had an average of 1.5 million unmapped reads (4.74%), more than the average 52,000 unmapped reads (0.16%) in the blood of healthy mice (p=0.000082). The lungs of critically ill mice had, on average, 194,331 unmapped reads (0.58%), which was more than the average 130,480 unmapped reads (0.39%) seen in the lungs of healthy mice (p=0.031665). In blood samples, unmapped reads from critically ill mice were less likely to be viral than healthy mice (average 3480 in critically ill vs. 4866 in healthy, p=0.025955). In lung samples, unmapped reads from critically ill mice were more likely to be viral than those from healthy mice (average 6959 in critically ill vs. 3877 in healthy, p=0.031959). The results were notable for higher viral loads in lungs of critically ill mice, showing that viral RNA loads can be a biomarker of critical illness.

Human correlates can translate into a clinical setting.

Example 3 Unmapped B/T V(D)J Use to Identify Sepsis

In immune systems, V(D)J recombination allows for a diversity of antibodies in B cells and T cell receptors in T cells. During critical illness, the variety of these recombination events reduces, but recovers. RNA sequencing better characterizes V(D)J recombination events. RNA sequencing shows more diversity in critical illness compared to what was described previously. B and T cell composition could prove to be an important marker in critical illness and predicting outcomes of sepsis.

The inventors subject mice (e.g., C57BL6 mice) to sequential of hemorrhagic shock followed by sepsis. This induces acute respiratory distress syndrome (ARDS). Lung and blood samples are collected. RNA from the samples is sequenced by next-generation sequencing. Reads from critically ill and healthy mice are aligned to GRCm38 annotation and then mapped to the V(D)J annotation by Read Origin Protocol (ROP).

In a third assay, the inventors recovered ˜thirty million reads were recovered from RNA-seq data generated from lung tissue of critically ill mice and healthy controls. Alignment with STAR aligner showed an average of 7.77% unaligned reads in the healthy control, and 8.78% unaligned reads in the samples extracted from critically ill mice. Unmapped reads then underwent a secondary alignment to assay for V(D)J recombinants. Healthy mice have an average of 629 recombinant epitopes, whereas critically ill mice had an average of only 208 recombinant epitopes. Assays were done in triplicate with littermates.

Analysis of unmapped reads shows that critical illness inhibits the generation of B cell and T cell epitopes by the immune system during critical illness. Although the percentage of unmapped reads between healthy mice and critically ill mice was not significant, the composition of B and T cell epitopes differs vastly in critically ill mice.

Example 4 Principal Component Analysis of RNA Splicing Entropy to Identify Sepsis

Next Generation Sequencing is useful for the diagnosis and treatment of diseases.

The effect of alternative RNA splicing before translation has not been studied much, especially in the critically ill patient. Previous work showed an association between cancer and the level of global alternative splicing entropy. Elias & Dias, Cancer Microenvironment, 1(1),131-9 (2008); Ritchie et al., PLoS Computational Biology, 4(3), e1000011 (2008). RNA splicing entropy is correlated with acute respiratory distress syndrome (ARDS) across multiple tissues. Evaluating splicing entropy can provide insights about biological processes and gene targets in the critical illness setting.

The inventors induce a mouse model of ARDS by subjecting mice to hemorrhagic shock, followed by cecal ligation and puncture. Blood and lung samples are collected from three mice undergoing ARDS and three sham controls. RNA is purified.

Next-generation RNA sequencing is performed. Alternative splicing (AS) entropy levels are determined using Whippet (v 0.11) on Julia (v 0.6.4). Principal Component Analysis (PCA) is conducted using base R (v 3.4.0). Alternative splicing events with a proportion of spliced in values between 0.05 and 0.95 are analyzed. A threshold of 1.5 is applied to determine the percentage of high entropy events. Proportions of high entropy events across tissues and experimental groups are compared using Mann Whitney U tests.

In a fourth assay, Principal Component Analysis of the blood samples was performed. Samples clustered based on tissue type and ARDS status on a Principal Component Analysis plot This result suggested that splicing entropy can serve as a biomarker for ARDS status. The inventors observed differential levels of splicing entropy across tissue types, with the most entropy in the lung.

Example 5 RNA Lariats to Identify Sepsis

This EXAMPLE demonstrates the collecting of RNA sequencing data from a complex tissue (blood), rather than a cell line, and uses computational biology techniques to analyze the data.

RNA splicing occurs directly after DNA transcription, but before protein translation. RNA splicing by a two-step esterification process with the formation of an intermediary lariat formed by the intron and joining of the 5′ and 3′ splice sites. Introns typically degrade rapidly.

The biology of lariats has recently been identified as important as it relates to viral biology. The DBR1 gene encodes for the only RNA debranching enzyme. Mutations of DBR1 increase susceptibility to HSV1 and increase viral brainstem infections in humans. Assessing the RNA lariat counts in the critically ill trauma patients could predict poor outcomes or prolonged immune suppression. The inventers undertook the mouse model of critical illness (CLP). Assessing for the resolution or return to a healthy level of lariat counts could be a marker to identify immune suppression or those patients at risk for a complication.

The identification of lariats from RNA sequencing data had been difficult. The William G. Fairbrother laboratory created a method to count lariats from RNA sequencing data. Taggart et al., Nature Structural & Molecular Biology, 19, 719-721 (2012).

In a fifth assay, the preliminary data suggests that in the critically ill mouse, the typical metabolism of RNA lariats is changed, resulting in an accumulation of lariats in the blood. The inventors found that the blood of mice with the critical illness have higher lariat counts compared to the control mice.

Example 6 Traumatic Shock

Lungs from healthy mice had an average of 3877 viral reads. Lungs from critically ill mice had on average 6956 viral reads. Blood from healthy mice had 4866 viral reads. Blood from critically ill mice had 3480 viral reads. Lungs from critically ill mice were more likely to have unmapped reads originating from viral genomes when compared to lungs from healthy mice (0.36% in critically ill, 0.21% in healthy; p-value=0.032). This could be due to critical illness leading to a compromised immune response that allows for viral reactivation and a higher viral load in lungs of critically ill mice. Traylen et al., Future Virol., 6(4), 451-63 (April 2011).

Blood of healthy mice were more likely to have unmapped reads originating from viral genomes than blood of critically ill mice (0.05% in critically ill, 0.11% in healthy; p-value=0.026). There are several explanations for why healthy mice could have increased viral loads in the blood compared to critically ill mice. Mature lymphocytes are constantly recirculating through blood and lymphatic organs. Charles et al., Immunobiol. Immune Syst. Health Dis. 5th Ed. (2001). In critical illness, the release of pro-inflammatory mediators may compound the intensity of immune surveillance, as documented in patients with systemic inflammatory response syndrome (SIRS). Duggal et al., Science Reports, 8(1), 1-11 (Jul. 5, 2018).

Change in leukocyte populations in critically ill mice may lead to a higher number of RNA-producing polymorphonucleocytes (PMN) in blood, which reduces the total viral RNA signal in critically ill mouse blood. Therefore, steps are taken to enrich for lymphocytes and monocytes to reduce RNA reads from PMNs.

This traumatic shock EXAMPLE demonstrated an association between critical illness and higher viral loads in mouse lung, lending promise to the clinical use of viral loads as a marker of critical illness.

Example 7 Processing RNA Sequencing Data to Aid in the Care of Sepsis Patients

More should be known about RNA biology, specifically alternative RNA splicing, in the sepsis population.

Over 90% of human genes with multiple exons require alternative splicing events to produce functional proteins. Pan et al., Nature Genetics 40, 1413-1415 (2008). RNA splicing creates a large natural source of variation of the transcribed gene to the produced protein product. RNA splicing is under exquisite control under normal conditions. Fever, hypothermia, and osmotic stress from fluid shifts can influence RNA splicing in vitro and change RNA splicing, altering protein expression. Gultyaev et al., TSitologiia i Genetika, 48, 40-44 (2014); Lemieux et al., PloS One 10, e0126654 (2015); Mahen et al., PLoS Biology 8, e1000307 (2010). Acidosis influences RNA splicing. Elias & Dias, Cancer Microenvironment, 1 131-139 (2008). Hypoxia also influences RNA splicing. Romero-Garcia et al., Experimental Lung Research 40, 12-21 (2014); Kasim et al., The Journal of Biological Chemistry, 289, 26973-26988 (2014). The effects of physiologic stress on RNA splicing should be better known. The pathological significance of changes induced RNA splicing process and proteins should be better understood.

This EXAMPLE shows the use of deep RNA sequencing data using computational biology methods (RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation) and apply these methods to three distinct data sets: mouse of different strains undergoing sepsis, deceased sepsis patients who participated in the GTEx project, and human sepsis patients.

RNA splicing entropy after sepsis. RNA splicing is a basic molecular function in all cells. This EXAMPLE uses the global index/marker of RNA splicing called ‘RNA splicing entropy’ a calculation of the precision of RNA splicing typically occurring. The entropy and thus the disorder, is maximal when the probability of all events P (x_(i)) is equally likely and the outcome is most uncertain. This calculation is done for each type of alternative splicing event: skipped exon, retained intron, alternative donor (3′ splice site), and alternative acceptor (5′ splice site). The alternative splicing events with high entropy are identified using Whippet.

A lower percentage of RNA slicing entropy may predict increased mortality or more complications, particularly infections, in patients with sepsis. Previous work on cancer samples has shown that RNA splicing entropy is increased in the tumor compared to the healthy tissue in many cancer types. From the preliminary data in mice with and without ARDS after sepsis, RNA splicing entropy is less in the blood, 7.7% vs 10.7%, p=0.1. RNA splicing entropy was calculated for total white blood cell components of mice with critical illness caused by hemorrhage and cecal ligation and puncture and compared to controls. The RNA from blood and the lungs of mice was extracted, processed, and then subjected to deep RNA sequencing.

Obtaining this data demonstrates the ability to isolate RNA samples from the target organ tissues of interest in the mouse model system. This EXAMPLE demonstrates the ability to process the complex data using computational biology and custom scripts that result from RNA sequencing. This preliminary data suggests that the process of RNA splicing in critical illness is different compared to the controls, changes in RNA splicing entropy may be a reflection/response to or a mechanism driving pathological processes that drive mortality and morbidity in patients with sepsis. Genes with significant alternative splicing and high entropy in the mouse after sepsis may be target for intervention. These genes of interest are identified using machine-learning techniques and compared across both humans and mice.

Assessment of viral activity after sepsis. In the initial assessment of RNA sequencing data, the reads are aligned to the genome of the species the sample came from. The unmapped reads can account for up to 20% of the data and this data is typically discarded. From this Read Origin Protocol analysis of multiple data sets (including GTEx data), the inventors found their protocol accounted for 99.9% of all reads. The data typically discarded was then analyzed in a seven-step process. Two of those steps are of particular interest because of the relevance to critical care: Viral reads and B and T cell receptor rearrangement.

Identification of viruses after sepsis is a marker of immune suppression since there is data suggesting sepsis re-activates herpes infections. Cook et al., Critical Care Medicine, 31, 1923-1929 ((2003)). Much current research is focused on these mechanisms and interventions. Viral counts could correlate with immune suppression or complications. This is important because of the re-activation data. RNA sequencing data from the lungs of control mice showed fewer viral reads (3877) compared to mice after sepsis (6956, p=0.032). In the blood the opposite was true. Control had 4866 counts versus sepsis with 3480 counts (p=0.026). This difference between tissue types could be due to a multitude of reasons, such as latent infections, like CMV, in the lung. Because blood is the most accessible tissue type, the efforts for the human samples should focus on the blood.

Assessment of immune cell epitopes after sepsis. During critical illness, the immune system is activated and likely creating new receptors to respond to challenges/pathogens. These epitopes come from lymphocytes, known to be reduced in sepsis with resolution to normal levels linked to recovery. Heffernan et al., Critical Care, 16, R12 (2012). While the count of lymphocytes themselves is useful, measuring the number and diversity of the epitopes could provide further insights into immune suppression after sepsis.

In the mouse model, preliminary data shows fewer epitopes in the lung of mice after sepsis, compared to control. This demonstrates the ability to analyze data from a mouse model and characterize B and T cell epitopes via computational methods. Like lymphocytes, the production of epitopes may reduce. Recovery should correlate with a return to normal immune state.

The above-described methods to assess for immune suppression in sepsis patients by analysis of RNA sequencing data to understand RNA biology are applied to these samples.

For analysis of RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation in the mouse model, using pilot data, using forty mice (twenty critically ill, twenty healthy controls) should have 80% power to detect a difference at a two-tailed alpha of 0.05. This method is used for each of the three mouse variants.

At the time points of twenty-four hours after cecal ligation and puncture and fourteen days after cecal ligation and puncture, mice are sacrificed, and organs procured. Organs to be collected are brain, lung, heart, kidney, liver, spleen, and blood. RNA from these samples is isolated as described below. The time point of twenty-four hours after CLP is selected as that is the time of most significant organ dysfunction. The time point of fourteen days is selected, since this is the point at which a mouse would be considered a survivor after this challenge.

RNA from blood samples in the mouse are processed using the MasterPure Complete RNA Purification (epicenter, Madison Wis., USA) kit for mice. Due to the high concentration of globin RNA in blood samples, these samples can then be further processed with the GLOBINclear Kit (epicenter, Madison Wis., USA). From blood one of skill in the molecular biological art can get 30-50 nanograms per microliter, with a total blood volume isolated from the mouse of about one mL. RNA from lung, heart, brain, kidney, liver, and spleen samples are extracted using MasterPure Complete RNA Purification kit for mice. After RNA samples are processed, the RNA was sequenced using standard techniques, for example by Deep RNA sequencing with a goal of 100,000,000 reads per sample. All samples should require at least 1400 nanograms of RNA for deep sequencing.

Human samples. Patients are recruited under Institutional Review Board approval and after consent is obtained. Blood samples are obtained from pre-existing catheters to minimize the risk. Blood samples are collected on admission and serially while the patient is in the intensive care unit. Samples are collected in PAXgene tubes and stored in an −80 C freezer until isolation of RNA for sequencing is needed. RNA sequencing is done in batches to minimize cost. For this experiment, it is expected 300 sepsis patients are recruited (average of 100 the first three years to allow analysis over the final two years of the project).

Control samples are obtained from healthy patients undergoing routine laboratory analysis at outpatient facilities. Blood from these patients is collected in PAXgene tubes and stored in an −80 C freezer until isolation of RNA for sequencing is needed. RNA sequencing is done in batches to minimize cost. Healthy controls are matched to sepsis patients based upon demographic/clinical data. Recruitment aims for 300 patients total (average 100 each year over the first three years). Sample size calculations for the recruitment of humans was done based upon initial results from the mice assays. Preliminary data from humans with sepsis shows more variation compared to the mice data. These differences from humans are accounted for by several things such as age, sex, medical co-morbidities, and variations in the timing of collection from the point of the sepsis.

RNA from blood samples from humans are processed using the MasterPure Complete RNA Purification (epicenter, Madison Wis., USA) kit for humans. Due to the high concentration of globin RNA in blood samples, these samples can then be further processed with the GLOBINclear Kit (epicenter, Madison Wis., USA). All samples require at least 1400 nanograms of RNA for deep sequencing, e.g., by Deep RNA sequencing with a goal of 100,000,000 reads per sample.

Genotype Tissue Expression (GTEx). The GTEx data has over 500 patients included with at least one sample that has undergone RNA sequencing. Extensive clinical data is available on these participants. The data can stratify the patients into early deaths (<36 hours) and late deaths (>36 hours). This classification and comparison between the groups was done as it highlights a population who could be intervened upon. The patients who die later die because of immune suppression leading to complications from sepsis. Earlier identification of immune suppression could change outcomes. The GTEx samples have been collected and undergone RNA sequencing. This sequencing data are analyzed as described above.

Innovativeness. RNA sequencing technology affords an avenue to bring precision medicine to sepsis patients. The inventors used blood samples from sepsis patients, process them and obtain RNA sequencing data of similar quality to that of cell lines or solid tissue samples. Monaghan et al., Shock, 47, 100 (2017). RNA sequencing allows for understanding not only the gene expression but also RNA biology. RNA is unstable compared to DNA. Kara & Zacharias, Biopolymers, 101, 418-427 (2014). RNA is influenced by the specific cellular environment (altered in sepsis).

Conceptual Innovation. Past work on sepsis and molecular mechanisms has been focused on gene transcription and protein expression. The process of alternative RNA splicing also can influence the expression of a protein independent of the gene expression. Chang et al., Combinatorial Chemistry & High Throughput Screening, 13, 242-252 (2010); Fredericks et al., Biomolecules, 5, 893-909 (2015).

By comparing findings in mice to humans using the publicly available RNA sequencing data from GTEx and human samples from the Intensive Care Unit, the inventors can establish the nature/type of RNA splicing common across species.

By determining the temporal relationship of changes in RNA splicing entropy, RNA lariats, viral identification, and B and T cell epitope creation with developing complications/mortality, the inventors can establish whether RNA biology can provide insight to immune suppression after sepsis.

Assessing information in the unmapped reads (viral and B/T cell epitopes) to determine clinical significance is using data that is typically discarded. This is like the use of lymphocyte counts to predict sepsis outcomes. Heffernan et al., Critical Care, 16, R12 (2012).

Technical innovation. RNA is isolated from complex tissues from both mice and humans. The isolate RNA is of high enough quality to allow for deep RNA sequencing. This analysis has only previously been done on cell line or cancer samples.

The inventors can use a series of analytical algorithms; initially, using the STAR aligner, then Whippet to assess and characterize splicing events and splicing entropy. This analysis is done across GTEx data, mice with sepsis and humans with sepsis.

The inventors can use the Read Origin Protocol as a basis. The inventors can modify as appropriate to assess viral content and B/T cell epitopes in data obtained from mouse models of sepsis, GTEx, and humans with sepsis.

The inventors can apply the scripts used previously to calculate lariat counts from RNA sequencing data. Taggart et al., Nature Structural & Molecular Biology, 19, 719-721 (2012). The RNA sequencing data is obtained from mouse models of sepsis, GTEx, and humans with sepsis.

Assaying the large amount of data that comes from RNA sequencing is commonly not successful due to several reasons. The analyses have biases for which controls are not in place, the large data should produce a statistically significant result but is it biologically and clinically significant. Using multiple biologic outputs (RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation) across three samples (GTEx, mouse model, and humans) mitigate.

By assaying RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation, one of ordinary skill in the molecular biological art can identify patients with this prolonged immune suppression.

Analyzing data already collected, such as using the GTEx data, and data like the unmapped reads from RNA sequencing supports creativity. This data would typically be ignored, but with the proper clinical relevance, the data can be reanalyzed and potentially find new biomarkers. The lymphocyte counts on a complete blood count with differential, a potential biomarker in the sepsis population. Heffernan et al., Critical Care, 16, R12 (2012).

Analysis of RNA sequencing data can provide one marker of the severity of the critical illness.

Evaluating RNA biology and outcomes after sepsis. Next generation RNA sequencing allows for the analysis of the RNA and assessment of not only gene expression but also other biological processes (alternative splicing, changes in transcription start and end). Correlating genomic information from high throughput sequencing technologies about a patient on arrival to the hospital with outcomes such as death and complications like infection should improve care. Since RNA is not as stable as DNA, assessing RNA are more sensitive to the physiologic stress in sepsis. The inventors can assess how the physiologic stress of sepsis influences RNA biology and alters proteins. Assaying RNA biology in critical care sepsis patients should translate to other patients with critical care after diseases.

By high throughput RNA sequencing the inventors can assay gene expression and the RNA processing events of alternative transcription start/end and alternative RNA splicing of from leukocytes in the blood. All three of these biological processes influence protein expression via generation of the RNA (gene expression), changing the beginning and end of the RNA (alternative transcription start/end), and changing the isoforms that are expressed (alternative RNA splicing). The combination of these three modalities creates a ‘transcriptomic phenotype’ and better identifies expressed proteins in the sepsis population as compared to the typical use of gene expression alone, compared to DNA, RNA is more influenced by the physiologic derangements seen in sepsis such as hypoxia and acidosis in cell culture. Elias & Dias, Cancer Microenvironment, 1(1),131-9 (2008); Kasim et al., The Journal of Biological Chemistry, 289(39), 26973-88 (2014).

In an intensive care unit, monitoring of physiology correlates to improved clinical outcome. Clinicians do not monitor how this physiology impacts RNA biology. Using high throughput sequencing, the inventors assay RNA biology in sepsis patients. The understanding of RNA biology at the time of injury should predict mortality, complications, and other outcomes in sepsis patients. Three aims are tested using a mouse model of sepsis, data from GTEx of sepsis patients, and blood from sepsis patients with correlation to outcomes.

Aim 1: Identify changes in RNA biology (gene expression, alternative transcription start/end, and alternative RNA splicing) in the blood before and after a pre-clinical mouse model of sepsis and compare to controls.

Aim 2: Using the data available from the Genotype Tissue Expression (GTEx) project correlate findings in the mouse model to these sepsis patients (81 patients).

Aim 3: Enroll critically ill sepsis patients and identify aspects of RNA biology that identify and predict outcomes (mortality, infection).

These analyses use data from high throughput sequencing and cloud computing to establish findings of RNA biology that correlate and predict outcomes in sepsis patients. This data comes from an ancestrally diverse sepsis population and can be applied to sepsis patients across the country and to multiple critically ill patient populations.

New technology has come that allows for analysis of all genes, not just those identified by the technology at the time. Tompkins, The Journal of Trauma and Acute Care Surgery. 78(4), 671-86 (2015). With RNA sequencing technology, particularly at the depth identified (80-100 million reads) needed for RNA biology assessment, the inventors can assess all genes transcribed, not just those identified as important with older technology. The analysis of all transcribed genes allows for the identification of genes that may be important for trauma, that in the past were overlooked, likely due to low transcription levels, with RNA sequencing technology the inventors can assay RNA biology (alternative transcription start/end and alternative RNA splicing), for a complete understanding of what genes are ultimately translated to functional proteins. Hardwick et al., Frontiers in Genetics, 10, 709 (2019).

Over 90% of human genes with multiple exons require alternative splicing events to produce functional proteins, creating a potentially large natural source of variation of the transcribed gene to the produced protein product. Pan et al., Nature Genetics, 40(12), 1413-5 (2008). Splicing is under exquisite control under normal conditions. Some conditions common in trauma, such as fever, hypothermia, and osmotic stress from fluid shifts can influence RNA splicing in vitro and change RNA splicing, altering protein expression. Gultyaev et al., TSitologiia i Genetika, 48(6), 40-4 (2014); Lemieux et al., PloS One, 10(5), e0126654 (2015); Mahen et al., PLoS Biology, 8(2), e1000307 (2010).

Using a mouse model of trauma caused by hemorrhage followed by cecal ligation and puncture, the inventors reported that alternative RNA splicing results in expression of varied isoforms of an immune modulating protein (programmed cell death receptor-1, PD-1). Preliminary data on RNA splicing entropy indicate that global RNA splicing is modified in the mouse model of trauma. Ritchie et al., PLoS Computational Biology, 4(3), e1000011 (2008). Increased RNA splicing entropy is also present in other pathologic conditions, such as cancers, as compared to normal tissue. Ritchie et al., PLoS Computational Biology, 4(3), e1000011 (2008). Increased entropy is characteristic of disease states and could be a marker of critical illness after sepsis.

Sepsis patients are a good population in which to assay critical illness and generalize the findings to other patients. A population of sepsis patients is an ideal group to assay genomic factors as previous research has been hindered by lack of racial and ethnic diversity. Multiple factors cause minorities to avoid healthcare. Chikani et al., Public Health Reports, 131(5), 704-10 (2016). By assaying sepsis patients, the inventors can collect data from a diverse population that is more in line with the general population and not the population that seeks healthcare. The findings are more generalizable, especially among an ancestrally diverse population.

Protocols for sepsis have improved outcomes. Rhodes et al., Intensive Care Medicine, 41(9), 1620-8 (2015). Sepsis can cause critical illness in a young population. The response to sepsis should not be influenced by co-morbidities associated with an increasingly aged population, but the inventors can collect co-morbidities to assess if there is an impact.

Genomic medicine is an ideal target for sepsis patients but is limited by sequencing technologies. Although genomic medicine is typically defined as using genomic information about an individual patient as part of their clinical care, this definition cannot be applied to sepsis patients or any critically ill patients.

Next generation RNA sequencing takes about 18 hours on an Illumina machine, but this does not include time for data analysis. Since the data are delayed until the outcome of the patient is known, data analysis can be blinded to allow for more robust conclusions, through this work, the efficiencies in computation biology can be elucidated so that when the sequencing technology speeds up, the analysis are quick enough to have a clinically relevant time frame (less than one hour) from sample acquisition to actionable result.

Thus, there is value in understanding of how stressors associated with sepsis can affect RNA biology (RNA splicing (and entropy) and alternative transcription start/end) and how changes in the RNA biology leads to altered protein product expression, contributing to potential dysfunction at a cell and tissue level.

Innovation. Past work focusing on trauma and molecular mechanisms has been focused on gene transcription and protein expression. The process of alternative RNA splicing and alternative transcription start/end both have the potential to influence the expression of a protein independent of the gene expression. Chang et al., Combinatorial Chemistry & High Throughput Screening, 13(3), 242-52 (2010); Fredericks et al., Biomolecules, 5(2), 893-909 (2015). By comparing findings in mice to humans using the publicly available RNA sequencing data from GTEx and human samples from the Trauma Intensive Care Unit the inventors can establish the nature/type of RNA biology that is common across species.

In determining the temporal relationship of changes in RNA biology with developing complications/mortality, the inventors can establish whether RNA biology can provide insight to immune suppression after sepsis.

Knowledge of RNA biology in the critically ill is useful because previous work on this process has focused largely on chronic diseases and genetic diseases.

The combination of gene expression, RNA splicing, and transcription start/end create a ‘transcriptomic phenotype’ that can be followed during the patients hospital stay.

RNA is isolated from complex tissues from both mice and humans. The isolate RNA is of high enough quality to allow for deep RNA sequencing. This analysis has only previously been done on cell line or cancer samples.

The inventors can use a series of analytical algorithms using the STAR aligner, then Whippet, to assess and characterize RNA biology. Results from Whippet are compared to mountainClimber to ensure accurate data as it pertains to alternative transcription start and end. This analysis is done across GTEx data, mice with sepsis and humans with sepsis.

Using multiple biologic outputs (alternative RNA splicing, including entropy, alternative transcription start/end) across three different samples (GTEx, mouse model, and humans in the trauma intensive care unit) should mitigate some of the potential flaws.

Preliminary data regarding trauma. In a small cohort of trauma patients from GTEx, three patients form the early death cohort (<48 hours) were compared to six patients from the late death cohort (>/=48 hours). In this comparison, 524 genes are significantly increased in the late death versus the early death. In the late death group, 2331 genes are decreased compared to the early death group. The GO terms associated with the genes that decreased expression in the late group compared to the early group are valid based upon previous research. The terms with a decrease in expected representation in the GO terms reference mitochondrial biology. This decrease in GO terms likely represents that genes are increased in expression at the early death time point. Mitochondrial molecular patterns have been a component of the early response to trauma and those genes would be increased in the early group. (37, 38) anemia occurs during trauma. In the late group, genes associated with erythrocyte development are over-represented, suggesting increase expression in the late death group compared to the early death group. These few GO terms and correlation to phenotypes of trauma, suggest use of early versus late death is a valid clinical tool. This preliminary data shows the ability to access, manage, and analyze GTEx data with clinically significant groups using modern computational biology techniques. Using GO terms allows us to prove clinical relevance. This project aims to obtain and analyze all the trauma samples from GTEx. The inventors can also use similar computational approaches with the prospectively collected data from trauma patients.

Multiple alternative RNA splicing events and alternative transcription start, and events are detected, but there are fewer that are significant. Using the same cohort as above, this preliminary date from GTEx data, alternative splicing and alternative transcription events are characterized using Whippet. Multiple events were identified to be alternative RNA splicing and alternative transcription start/end in the blood samples. When comparing the groups there were only significant differences when assessing alternative RNA splicing and not alternative transcription start and end. This data confirms that alternative RNA splicing is an active process during trauma and could predict mortality and outcomes in trauma patients, genes with changes in splicing, and potentially transcription start/end could identify useful targets. The combination of gene expression, splicing and transcription start/end could alter what proteins were thought to have increased gene expression and subsequent protein transcription have altered processing resulting in new isoforms or changes in transcription. These findings highlight the ability to access GTEx data, categorize the samples in a clinically relevant manner, and process the RNA sequencing data with advanced computational methods, such as Whippet.

RNA splicing, specifically RNA splicing entropy shows differences after trauma. From the preliminary data in mice with and without, the inventors can show that in the blood there is less RNA splicing entropy, 7.7% versus 10.7%, p=0.1. RNA splicing entropy was calculated using Whippet. The percentage of each type of splicing event with an entropy of >1.5 (Alternative Donor, Alternative Acceptor, Retained Intron, and Skipped Exon). Using the mouse model of trauma, RNA splicing entropy was calculated for total white blood cell components of mice after trauma caused by hemorrhage with cecal ligation and puncture (n=3) and compared to controls (n=3). The RNA from blood was extracted, processed, and then subjected to deep RNA sequencing. This preliminary data suggests that the process of RNA splicing in critical illness is different compared to the controls, changes in RNA splicing entropy may be a reflection/response to or a mechanism driving pathological processes that drive mortality and morbidity in patients with trauma. Obtaining this data demonstrates the ability to isolate RNA samples from the target organ tissues of interest in the mouse model system. This EXAMPLE demonstrates the ability to process the complex data using computational biology and custom scripts that result from RNA sequencing.

The trauma patients in the intensive care unit provide an ancestrally diverse population and adequate numbers to correlate mortality and other complications. The trauma intensive care unit admits over 750 patients a year with 20% of those patients coming from an ancestrally diverse background. The enrollment is in line with the general population, even though underrepresented minorities seek medical care at a reduced rate. One aspect to this invention is the correlation of the RNA sequencing data to mortality and complications.

This EXAMPLE shows the importance of not only predicting mortality, but also using RNA sequencing data to predict complications as patients with complications had a higher mortality (7.7%). Mortality could be influenced. This data shows the trauma center has the volume of patients in the intensive care unit to have an appropriately powered study.

Over four years, 520 patients can be enrolled based on sample size calculations, with fewer than the 3000 expected admissions proving feasibility.

TABLE 4 Aim Suggested Type of Research Application 1 Integration of other data types, A model organism (mouse such as environmental data, family after trauma) will provide history, transcriptomics, the basis for other epigenomics, functional data, or analyses in humans after model organism data to improve trauma. Multiple strains assessment of clinical validity or will mimic the diverse clinical utility of genomic human population. information. 2 Assessment of improved GTEx data are re-analyzed approaches for reanalyzing patient using modern approaches and genomic data and understanding a unique population (early its impact on clinical care. versus late trauma deaths) 3 Evaluation of modern approaches Trauma patients will provide to interpreting genomic data in an ancestrally diverse ancestrally diverse populations in population to assay this clinical settings clinical genomic date.

This approach uses RNA sequencing data from a mouse model of trauma, re-analysis of existing genomic data in GTEx about early versus late trauma deaths, and samples from ancestrally diverse critically ill trauma patients uniquely suited to provide clinical information applicable across many clinical scenarios, particularly critically ill patients with cancer, sepsis, stroke, or myocardial infarction. The analysis of the RNA data from next generation sequencing technology creates a ‘transcriptomic phenotype’ for each trauma patient. Understanding the RNA biology at the time of injury can predict outcomes (mortality and complications) in trauma patients. The method to test the three aims, the expected result, and the potential impact are summarized in TABLE 5.

TABLE 5 Aim Method Result Impact 1 Mouse model of Changes in RNA biology These findings provide the trauma, assessing predict mortality after the foundation for predicting blood before mouse model of trauma. mortality and complications trauma, after The results seen at 24 in critically ill trauma trauma, and in hours differ from those patients. Data seen at 24 survivors identified at 14 days. hours and 14 days correlate with patients who die early versus late. 2 81 deceased Changes in RNA biology This are the foundation for trauma patients are identified in early analysis of RNA data from from GTEx, 23 versus late trauma deaths trauma patients during their early deaths and and these correlate with hospital stay. 58 late deaths mouse data. 3 Critically ill trauma Changes in RNA biology Using RNA sequencing data patients assessing on admission predict predict mortality and blood on complications and complications and enhance admission and mortality. changes over care of trauma patients with throughout course the hospital course applicability to all intensive correlate with long-term care unit patients. outcomes.

Aim 1: Identify changes in RNA biology (gene expression, alternative transcription start/end, and alternative RNA splicing) in the blood before and after a pre-clinical mouse model of trauma and compare to controls.

Rationale: to determine if altered RNA biology in its various forms can predict outcomes, RNA sequencing data must be collected at various time points during the traumatic injury. The inventors can establish the equivalency of such a pre-clinical animal model to what is encountered clinically. The inventors previously used a mouse model of hemorrhagic shock followed my septic shock by cecal ligation and puncture (CLP). Monaghan et al., J. Transl. Med., 14(1), 312 (2016). This mouse model mimics a trauma patient with hemorrhagic shock from an extremity injury who then had a missed bowel injury resulting in severe critical illness. Using this mouse model, the inventors can obtain blood at the initial injury and assess if changes in RNA biology, to predict mortality from the severe trauma model. Using a mouse model allows for acquisition of blood samples at multiple time points (twenty-four hours after injury and in those mice that survived). The inventors can first assess if RNA biology in the blood can predict mortality, if changes in RNA biology are seen twenty-four hours after injury, and how these correlate to the RNA biology of survivors at fourteen days.

Test 1: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end to develop the ‘transcriptomic phenotype’ from shed blood in the mouse model of trauma to predict outcomes. Mice (8-12 weeks old) undergo hemorrhagic shock followed by CLP to mimic the critical illness that a trauma would undergo after hemorrhagic shock from an extremity injury complicated by a missed small bowel injury. Mice are used from the background of C57BL/6J, BALB/cJ, and CAST to simulate the heterogeneity of humans. Each group has twenty-four (twelve sham and twelve trauma) mice for each strain based upon statistical calculations. C57BL/6J mice have a 30% survival at fourteen days. The shed blood from the hemorrhage component is collected. Although this blood is collected before the effects of hemorrhage, this time point can mimic an early time point in trauma, since the mice have undergone anesthesia and isolation/catheter insertion of the artery. RNA is isolated, sequenced and analyzed as described. The mice that survive to fourteen days can also be sacrificed and used in Test 2.

Test 2: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end to develop the ‘transcriptomic phenotype’ from the blood of mice at twenty-four hours and fourteen days after trauma. Mice (8-12 weeks old) undergo hemorrhagic shock followed by CLP to mimic a severe trauma. Mice are used from the background of C57BL/6J, BALB/cJ, and CAST. Mice are sacrificed at twenty-four hours after CLP. Mice that survive to fourteen days are also sacrificed to assess RNA biology at that point among the survivors. Appropriate controls for each type of background mice undergo sham procedures. Based upon previous work, six mice are needed for each group. After mice are sacrificed (CO₂ overdose followed by direct cardiac puncture) at either twenty-four hours or fourteen days after CLP blood are harvested. RNA from blood samples in the mouse are processed.

Human samples. Through collaboration with the military, soldiers in combat areas could be consented to donate blood before deployment. This blood would then undergo RNA sequencing and be compared to samples collected if there was an unfortunate traumatic injury. Many previous efforts using animal models to treat diseases such as sepsis failed to translate to humans. Fink & Warren. Nature Reviews Drug Discovery, 13(10), 741-58 (2014). The inventors previously studied conditions in mice with correlation to humans. Monaghan et al., J. Transl. Med., 14(1), 312 (2016); Monaghan et al., Molecular Medicine, 24(1), 32 (2018); Monaghan et al., Journal of the American College of Surgeons, 213(3), S54-S5 (2011); Monaghan et al. Annals of Surgery 255(1), 158-84 (2012). Trauma research may have better translatable results because of the timing of the disease. In trauma, the time of the event is known. This timing correlates with the induced trauma in the mouse. In sepsis, the time point at which sepsis started in the mouse is known. In humans, the time at which sepsis starts is impossible to know, as exemplified by inability to understand when an appendix may perforate. Iacobellis et al., Seminars in Ultrasound, CT, and MR, 37(1), 31-6 (2016). This is limited because it is a controlled traumatic challenge and should produce very consistent response to trauma. In humans, no trauma is the same. The number of humans needed to detect a difference is more since the traumas are not similar. Humans have more heterogeneity adjusted for by using multiple mouse strains. The inventors can account for differences in trauma by using the Injury Severity Score. The ISS of this challenge on the mouse is twenty-five, and this is the target average ISS of patients enrolled.

Aim 2: Using the data available from the Genotype Tissue Expression (GTEx) project correlate findings in the mouse model to these trauma patients (eighty-one patients).

Rationale. Using the GTEx data, the inventors can assess RNA biology in the blood of trauma patients. The GTEx data has over 500 patients included with at least one sample that has undergone RNA sequencing. The patients in the GTEx data set have extensive clinical data available. Unfortunately, all patients in this data set are deceased. This should be considered in interpretation of the data. To adjust for the fact all patients are deceased, the inventors use the time to procurement of the RNA from the death of the patient as a variable due to adjust for RNA degradation and other metrics as suggested by the GTEx consortium. (50) Trauma patients are selected (n=81) and identified as early (<48 hours) versus late death (>/=48 hours). The inventors can compare RNA biology between trauma patients who died early versus late and compare it to findings in a mouse model of mice who died early (twenty-four hours) versus survivors (fourteen days)

Test 1: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end to develop the ‘transcriptomic phenotype’ the blood of deceased trauma patients and compare among early and late deaths. There are 81 unique trauma patients in the data set with blood samples. These patients are aged 20-68, in line with the age of typical trauma patients. The GTEx samples have been collected and undergone RNA sequencing. RNA sequencing data are aligned to the human genome with STAR. RNA Splicing events are assessed using Whippet and characterized into one of the five alternative splicing events: skipped exon, retained intron, mutually exclusive exon, alternative 3′ splice site, and alternative 5′ splice site. Entropy calculations are completed using Whippet. Alternative transcription events from Whippet are compared to outputs from mountainClimber.

Test 2: Correlation of changes in expression, alternative RNA splicing, and alternative transcription start/end (the ‘transcriptomic phenotype’) in the blood of humans to the mouse samples. From mouse model (Aim 1) changes in expression, alternative RNA splicing, and alternative transcription are identified and these are compared to findings in the human GTEx data (Aim 2, Test 1). The mouse model data are taken from mice at twenty-four hours after CLP and at fourteen days after CLP. This data is compared to the human data of early (<48 hours) and late (>/=48 hours) death. The identical genetic background of laboratory mice (despite coming from three strains) allows for assumptions to be made about significance of changes at a higher resolution, due to the certainty of the genetic model. Simultaneously it creates uncertainty about the validity of findings, due to a lack of comparability to humans that experience conditions outside of the laboratory. Human data is plagued by an equal and opposite effect as data derived from animal models. The homogeneity of the mouse model is replaced with heterogeneity due to factors such as age, sex, co-morbidities, and differences in the trauma. By coupling the certainty provided by the homogeneity of the mouse model, and the uncertainty provided by the heterogeneity of the human model, the inventors create a powerful tool with the potential to validate results from mouse analyses in humans. Comparing events across species can identify RNA biology events and genes that are important at both the early and late time point. These findings are compared to those found in the prospective collected data from trauma patients.

Human samples. In this sample set, all the patients are dead. Since RNA is unstable compared to DNA, adjustments in the comparisons between groups during the analysis must be made for the time it took for samples to be collected and RNA isolated. The mouse work is comparing to mice that are alive but were sacrificed. The GTEx consortium, to adjust for problems associated with deceased donors, has described multiple methods. Carithers et al., Biopreservation and Biobanking, 13(5), 311-9 (2015).

Aim 3: Enroll critically ill trauma patients and identify aspects of RNA biology that identify and predict outcomes (mortality, infection).

Rationale: A current challenge with the data from the animal models is ensuring translation to humans. This aim allows for complete translation of mouse data to humans. The human population of interest are patients admitted to the Trauma Intensive Care Unit (TICU).

Test 1: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end in the blood can be prospectively detected and use this ‘transcriptomic phenotype’ in trauma patients on arrival and be correlated to mortality. Trauma patients are recruited from the trauma intensive care unit, which has an average of over 750 patients, admitted each year (over the last three years) and an average injury severity score (ISS) of 13, but the goal is to enroll patients with an average ISS of 25 to mimic the mouse model. Blood is collected in PAXgene tubes and stored at −80 C after informed consent is obtained. Samples are collected serially while in the ICU. Blood samples from patients are taken on admission (25 mL) and during the TICU stay when a complication is developed (25 mL). This causes the maximum for the initial 8-week period after the trauma. When the patient is recovered, at least eight weeks after the last blood draw, a final blood draw 50 mL of are done, potentially in the outpatient setting. Patients who survive the trauma are compared to patients who died. Clinical information for the trauma patients is collected from the trauma registry. The trauma registry is a database required as part of verification by the American College of Surgeons to be a trauma center. The data are standardized across the entire recruitment period. RNA is isolated using the PAXgene RNA Kit. RNA was sequenced (goal 80 to 100 million reads). RNA sequencing data are aligned to the human genome using the STAR aligner. Changes in expression, alternative RNA splicing, alternative transcription start/end, and RNA splicing entropy are identified with Whippet. Alternative transcription findings are correlated with mountainClimber.

Test 2: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription starts and end in the blood can be prospectively detected in trauma patients on arrival and use the ‘transcriptomic phenotype’ to correlate to outcomes and complications. Patients from the trauma intensive care unit identify differences in RNA biology between the healthy controls and trauma patients predict outcomes and complications. Outcomes and complications are recorded from the medical record and are defined in the trauma registry (and decided by trained coders). The trauma registry provides some demographic data, such as injury severity score to better quantify and adjust for the severity of the trauma across patients. Outcomes to follow and use as potential for prediction include mortality, hospital length of stay, intensive care unit length of stay, ventilator free days, and discharge disposition. Complications to be recorded again are taken from the trauma registry and include items such as infections (pneumonia, surgical site infections, urinary tract infection, bacteremia, sepsis), unplanned return to the operating room, unplanned return to the intensive care unit, tracheostomy, and feeding tube placement.

Human samples: In this sample set, all the patients are critically ill. Consenting patient who are critically ill requires a proxy and this can sometimes be difficult in the unexpected nature of trauma. The inventors have past success in consenting these patients. Human heterogeneity may make finding a significant difference between two groups difficult. Drastic difference (trauma patients in the intensive care unit survive versus die and those with complications) should allow for the identification of differences in RNA biology (‘transcriptomic phenotype’). All samples for this assay come from living patients.

Example 8 Survival Assay

All the test mice have the traumatic injury. They are maintained for fourteen days. At fourteen days all mice are sacrificed. The survival rate at fourteen days for the double hit model is 30%. The rate goes up to 70%. Monaghan et al. Annals of Surgery 255(1), 158-64 (2012). These estimates result in an effect size of h=0.823. A sample size of twenty-four per group during analysis would exceed 80% power at a 2-tailed alpha of 0.05 by a chi-square test of independent proportions, for survival analyses the inventors use twenty-four mice per group. This are done to ensure enough power to detect if RNA splicing at the initial challenge can predict survivors. Sham mice are operated (8 from each mouse background strain) at this time to procure samples at the 14-day time point.

RNA isolation and sequencing. RNA data from GTEx is extracted and sequenced per their protocols. RNA from mouse blood samples is processed using the MasterPure Complete RNA Purification (epicenter, Madison Wis., USA) kit for mice. Due to the high concentration of globin RNA in blood samples, these samples then be further processed with the GLOBINclear Kit (epicenter, Madison Wis., USA). From blood the inventors can get approximately 30-50 nanogram per microliter, with a total blood volume isolated from the mouse of about one mL. After RNA samples are processed, they are sequenced. All samples require at least 1400 nanograms of RNA for deep sequencing. Each sample are sent out (due to advancing technologies, costs of sequencing change frequently, therefore outside facility are chosen based upon cost during sample send out) for Deep RNA sequencing with a goal of 80 million to 100 million reads per sample.

Blood from trauma patients and healthy human control samples are collected using the PAXgene tubes (PreAnalytiX, Switzerland) and isolated using the PAXgene RNA kit (PreAnalytiX, Switzerland). Since it is impossible to predict the patients who die or have a complication on admission to the ICU, banked samples are used since the cost to perform RNA sequencing on the blood of all TICU patients at Rhode Island Hospital is impossible.

Assessment of clinical information. Clinical data relevant to the patient samples are collected from the trauma registry and the electronic medical record. This allows for collection of endpoints such as mortality. ICU length of stay, hospital length of stay, ventilator days, renal failure, ARDS, pneumonia, and other infectious complications. Besides data in the chart, the inventors also perform functional assessments at follow up after discharge. These would be based upon previous work in critical illness and use the 36-item short form (SF-36). The assessment is done at the 8+ week follow up.

Example 9 Alternative RNA Splicing and Alternative Transcription Start/End in Acute Respiratory Distress Syndrome

The objective of this EXAMPLE is to use RNA sequencing data and analysis to identify useful gene targets in sepsis.

Alternatively spliced RNA arises from co/post-transcriptional events facilitated by the spliceosome, introns are removed to form the mature RNA from which protein isoforms are translated. Alternatively transcribed genes are the product of changes in promoter usage, polyadenylation signals, and RNA polymerase II interactions with DNA which can lead to changes in isoform usage like alternative splicing events. These are identified from the analysis of RNA sequencing data. Significant differentially alternatively transcribed genes and alternative spliced genes were identified and were overlapped with genes reported as ARDS related. See, Reilly et al., American Journal of Respiratory and Critical Care Medicine (2017). Of 89 reported ARDS related genes, 38 were confirmed in at least one differential category confirming that the use of humans and mice with DAD/ARDS is appropriate and robust (p=1.25e−14). Eleven previously reported genes were present in all categories. These eleven genes were evaluated for the change in alternative splicing and alternative transcription GO term enrichment analysis was performed on the eleven overlapping genes, revealing twenty significant biological processes including ontology related to aging, and response to abiotic/environmental stimuli. See FIG. 1. 1639 genes show overlap in alternative splicing and alternative transcription not previously in the literature. These genes were assessed for directionality alternative splicing and alternative transcription and GO terms. See TABLE 3 and TABLE 4.

Assaying the underlying changes in RNA processing (alternative splicing and alternative transcription start/end) not expands basic knowledge only of pathogenicity, but also provides additional targets for therapeutics. The most enriched GO term from the alternative splicing set, carboxy-terminal domain protein kinase complex (GO: 0032806) refers to phosphorylation of the CTD of RNA polymerase II, which is vital in regulating transcription and RNA processing. RNA polymerase complex binding (GO: 0000993), and transport of the SLBP Independent/Dependent mature mRNA (R-HSA-159227; R-HSA-159230) are among the most enriched. Alternative pre-mRNA splicing may have the dominate role in isoform usage in genes where expressions levels do not change, whereas alternative transcription may regulate isoform usage in genes that are more dynamically expressed during critical illness. Alternative splicing and alternative transcription may have separate roles in DAD/ARDS by regulating different genes to perform distinctive functions.

In this analysis of RNA sequencing data from deceased patients with ARDS identified by DAD and a clinically relevant mouse model of ARDS, useful genes are identified.

Overview. The inventors used RNA sequencing to identify changes in mRNA processing events (RNA splicing and transcription start/end sites) can be studied with RNA sequencing data. The inventors' strategy was to use the contrast how the processing of mRNA changes in lung and blood of patients with ARDS and compare to the lung and blood of a mouse model of ARDS.

Data. For this EXAMPLE, two main approaches were taken to obtain samples. The first was to use a validated mouse model of ARDS. Ayala et al., The American Journal of Pathology, 161, 2283-2294 (2002); Monaghan et al., Molecular Medicine (Cambridge, Mass., USA), 24, 32 (2018). All experiments were done according to guidelines from the National Institutes of Health (Bethesda, Md.). For the mouse model of ARDS. C57BL/6 male mice (The Jackson Laboratory, Bar Harbor, Me., USA) between 10 and 12 weeks of age were used. ARDS was induced in the mice by hemorrhage (non-lethal shock) followed by cecal ligation and puncture (CLP). The control group was sham hemorrhage followed by sham CLP.

The second approach was to identify patients in the GTEx Project with ARDS. All patients in the GTEx projects used in this EXAMPLE are deceased. A pathologist, blinded to the specimen ID and history, identified diffuse alveolar damage in lung samples from patients in GTEx. Most cases of clinical ARDS have diffused alveolar damage (DAD) morphologically. Zander & Farver, Pulmonary pathology e-book: A volume in foundations in diagnostic pathology series. (Elsevier Health Sciences, 2016). Classic DAD was identified based histologic features (For full description, please see supplement). Patients with evidence of diffuse alveolar damage in the lung and a corresponding blood and lung sample that had undergone RNA sequencing were placed in the ARDS group. Patients who had no evidence of diffuse alveolar damage in the pathology sample and a blood and lung sample with RNA sequencing were placed in the control group. Most cases of clinical acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) have diffused alveolar damage (DAD) morphologically, which is divided into 2 phases: the acute/exudative phase and the organizing/proliferative phase. Other histologic patterns encountered in a clinical setting of ALI/ARDS include diffuse alveolar hemorrhage, acute eosinophilic pneumonia (AEP), and the acute fibrinous and organizing pneumonia (AFOP). Eight patterns of acute lung injury are evaluated in this EXAMPLE. Zander & Farver, Pulmonary pathology e-book: A volume in foundations in diagnostic pathology series. (Elsevier Health Sciences, 2016). Classic DAD was graded 1-4 based on the histologic features. Other patterns of injury were scored using a semiquantitative system for extent and histologic characteristics. For extent, grade was assigned: grade 1 (1 point): up to 10% tissue involved, grade 2 (2 points): 11-30% tissue involved, grade 3 (3 points): 31-50% tissue involved and grade 4 (4 points): >50% tissue involved. Histologic characteristics including intra-alveolar fibrin (1 point), cellular alveolar debris (I point), type II pneumocyte hyperplasia (1 point) and capillaritis/vasculitis. Total points 6 or higher were considered as DAD. Despite this complex method for categorizing diffuse alveolar damage, using this to diagnose ARDS is a major limitation. DAD could be present in other pulmonary diseases. The value RNA sequencing data from the lungs and blood of patients can provide biologic insights despite these limitations.

Results. Alternative splicing events were observed at 2-fold higher abundance as compared to alternative transcription events, yet significant alternative transcription events between groups were observed at a 6-fold higher prevalence (p=2.2e−16). Eighty-two alternative transcription events were common across all ARDS tissues (human and mouse, blood and lung, p=2.72e−16). No significant alternative splicing events were detected across all four tissues. As alternative splicing is species and tissue specific, it is unlikely to find an event that occurs in lung tissue and blood tissue in both human and mouse. GO term analysis was also performed on the significant differentially processing events.

The full list is TABLE 3 and TABLE 4 in International patent application PCT/US2021/018218, which are incorporated by reference.

Example 10 SARS-CoV-2 Viral Load and Nucleic Acid-Based Antiviral Therapies (RIH #332).

This invention disclosure describes a specific diagnostic. Determining which COVID-19 patients are at risk for severe disease and developing better anti-coronavirus therapies are clinical priorities. The invention leverages new information from genomic studies that demonstrate very limited, highly-specific regions of the SARS-CoV-2 genome are transcriptionally active in the bloodstream of COVID-19 patients. The invention solves the problem of measuring viral load in the blood from infected patients to assess prognosis. Viral load measurements are central to the management and prognosis of patients with HIV infection. The inventors found that using SARS-CoV-2 viral load to identify patients with more severe COVID-19, track the disease's course, and follow the response to treatment. The same sequences are used to create antiviral, interfering RNAs that block viral gene expression specific for viremia. This therapy directly blocks genes for COVID-19 pathogenesis. The invention is superior to potential competitors because the genomic data informs the design of relevant oligonucleotides that increases the assay's sensitivity.

The invention measures the amount of SARS-CoV-2 circulating in patients' blood. This amount is elevated in patients critically ill with COVID-19. The results therefore provide information on the prognosis of individual patients. Interfering RNA that specifically targets these sequences reduce these genes' expression, interrupting viral replication and the downstream consequences of COVID-19. The open reading frame encoding the N protein also includes ORF9b, which has been shown to antagonize the action of antiviral type I interferon. Blocking this region of the virus enhance the host's endogenous antiviral response.

The invention can be used by all clinicians caring for COVID-19 patients. High or increasing SARS-CoV-2 viral loads identify those at the most significant risk for severe disease. The therapy is unique compared to those approved or under clinical trial.

Example 11 Deep Sequencing to Identify Targets for Detecting and Treating Pathogens

This invention disclosure describes a more general approach. Diagnostic testing for specific infections depends on a substantial understanding of the underlying pathogen. Nucleic acid amplification tests (NAT) are increasingly used in clinical medicine, but developing a test is time-consuming and may miss NAT's optimal sequences. In the setting of a new pandemic like COVID-19, delays can be fatal. This invention leverages further information from deep sequencing of RNA from patients with specific infections to develop diagnostic targets and therapeutic strategies. Deep sequencing of RNA identifies the pathogen's most abundant RNA transcripts that establish a future work foundation. The approach is especially valuable for new pathogens poorly characterized because the RNA sequencing is unbiased and analyze known and unknown sequences.

The findings with SARS-CoV-2 illustrate the invention's potential. The sequencing studies demonstrate that very limited, highly specific regions of the SARS-CoV-2 genome are transcriptionally active in the bloodstream of COVID-19 patients. The invention solves the problem of measuring viral load in the blood from infected patients to assess prognosis. Viral load measurements are central to the management and prognosis of patients with HIV infection. The inventors found that using SARS-CoV-2 viral load to identify patients with more severe COVID-19, track the disease's course, and follow the response to treatment. The same sequences can be used to create antiviral, interfering RNAs that block viral gene expression specific for viremia. This therapy directly blocks genes for COVID-19 pathogenesis. The invention is superior to potential competitors that focus on DNA sequencing, which misses all possible RNA viruses like SARS-CoV-2 and influenza. Testing the most abundant RNA sequences enhance diagnostic assays' sensitivity because there can be more target sequences to measure.

The invention is a technical approach to measure pathogen RNA expression circulating in patients' blood. Computational analysis identities sequences, and these sequences can be used to develop diagnostic tests and therapeutics, such as small interfering RNAs mentioned above.

The invention can be used by academic and industry researchers who study infectious diseases pathogenesis, diagnostics, and treatment.

Example 12 RNA Sequencing to Assess Bacterial Gene Expression of Bacteria in the Human Host During Sepsis

Attached are the genes and counts from Acinetobacter in a patient with COVID-19. The genes with the most counts are listed. Bact Gene Exp. The Out CSEQS=Aligned out bam.

TABLE 6 Out Gene id Chr Start End Strand Length CSEQS IX87_RS10825 NZ_CP009257.1 2143428 2144498 − 1071 6072 IX87_RS13765 NZ_CP009257.1 2731324 2733000 − 1677 1621 IX87_RS06655 NZ_CP009257.1 1293290 1295281 + 1992 1486 IX87_RS04495 NZ_CP009257.1 875468 876043 + 576 1480 IX87_RS01665 NZ_CP009257.1 311888 312541 − 654 1213 IX87_RS06455 NZ_CP009257.1 1241219 1243858 − 2640 1151 IX87_RS13760 NZ_CP009257.1 2729698 2731236 − 1539 1120 IX87_RS18095 NZ_CP009257.1 3641468 3641941 + 474 1009 IX87_RS14290 NZ_CP009257.1 2840814 2842754 − 1941 1008 IX87_RS09870 NZ_CP009257.1 1960173 1963025 − 2853 995 IX87_RS01755 NZ_CP009257.1 329174 331312 − 2139 986 IX87_RS09635 NZ_CP009257.1 1887997 1889631 − 1635 879 IX87_RS22220 NZ_CP009257.1 1932345 1948691 − 16347 875 IX87_RS17835 NZ_CP009257.1 3585533 3587203 + 1671 856 IX87_RS02170 NZ_CP009257.1 400923 402596 − 1674 842 IX87_RS10110 NZ_CP009257.1 2012821 2014125 − 1305 829 IX87_RS11740 NZ_CP009257.1 2326862 2327869 − 1008 819 IX87_RS09895 NZ_CP009257.1 1967878 1969152 + 1275 806 IX87_RS15045 NZ_CP009257.1 3003563 3004957 + 1395 801 IX87_RS09420 NZ_CP009257.1 1842311 1843243 − 933 768 IX87_RS06650 NZ_CP009257.1 1292234 1293286 + 1053 764 IX87_RS17750 NZ_CP009257.1 3567691 3569478 + 1788 758 IX87_RS10025 NZ_CP009257.1 1992002 1995178 + 3177 737 IX87_RS06640 NZ_CP009257.1 1288710 1291097 + 2388 735 IX87_RS04550 NZ_CP009257.1 885563 886978 − 1416 693 IX87_RS08840 NZ_CP009257.1 1721583 1723820 − 2238 686 IX87_RS20710 NZ_CP009257.1 4164453 4166039 + 1587 683 IX87_RS15035 NZ_CP009257.1 3001041 3002585 + 1545 671 IX87_RS15670 NZ_CP009257.1 3126337 3130530 + 4194 669 IX87_RS17765 NZ_CP009257.1 3571341 3574025 + 2685 641 IX87_RS15665 NZ_CP009257.1 3122162 3126250 + 4089 621 IX87_RS17795 NZ_CP009257.1 3578320 3579918 + 1599 591 IX87_RS09425 NZ_CP009257.1 1843261 1844010 − 750 586 IX87_RS09880 NZ_CP009257.1 1964309 1966144 − 1836 574 IX87_RS15625 NZ_CP009257.1 3116997 3118187 + 1191 571 IX87_RS09760 NZ_CP009257.1 1921690 1924920 + 3231 565 IX87_RS15755 NZ_CP009257.1 3145473 3147626 − 2154 557 IX87_RS09730 NZ_CP009257.1 1915821 1917716 − 1896 553 IX87_RS06375 NZ_CP009257.1 1227725 1228243 − 519 542 IX87_RS13365 NZ_CP009257.1 2644473 2647190 − 2718 528 IX87_RS07930 NZ_CP009257.1 1538290 1539705 − 1416 517 IX87_RS12725 NZ_CP009257.1 2519255 2520769 + 1515 502 IX87_RS09860 NZ_CP009257.1 1957481 1958914 − 1434 494 IX87_RS02825 NZ_CP009257.1 524251 525132 + 882 491 IX87_RS11765 NZ_CP009257.1 2329533 2330852 − 1320 479 IX87_RS08365 NZ_CP009257.1 1609789 1610940 + 1152 470 IX87_RS00340 NZ_CP009257.1 44564 45673 + 1110 467 IX87_RS13230 NZ_CP009257.1 2616298 2617083 + 786 467 IX87_RS01760 NZ_CP009257.1 331491 331961 − 471 466 IX87_RS15655 NZ_CP009257.1 3120936 3121442 + 507 466 IX87_RS09465 NZ_CP009257.1 1852062 1853039 + 978 463 IX87_RS07885 NZ_CP009257.1 1533357 1533983 + 627 458 IX87_RS00325 NZ_CP009257.1 40294 42723 + 2430 456 IX87_RS04585 NZ_CP009257.1 893625 896204 − 2580 454 IX87_RS10860 NZ_CP009257.1 2150015 2152420 − 2406 450 IX87_RS02405 NZ_CP009257.1 443230 446997 + 3768 444 IX87_RS09605 NZ_CP009257.1 1880229 1881134 + 906 444 IX87_RS17680 NZ_CP009257.1 3556213 3559047 − 2835 434 IX87_RS17800 NZ_CP009257.1 3579921 3581417 + 1497 430 IX87_RS01685 NZ_CP009257.1 315690 316502 + 813 418 IX87_RS07790 NZ_CP009257.1 1508072 1508824 − 753 409 IX87_RS06320 NZ_CP009257.1 1215830 1217341 + 1512 405 IX87_RS13990 NZ_CP009257.1 2775687 2778371 + 2685 401 IX87_RS07865 NZ_CP009257.1 1527434 1529704 + 2271 400 IX87_RS11565 NZ_CP009257.1 2291470 2292456 − 987 399 IX87_RS09855 NZ_CP009257.1 1956167 1957333 − 1167 395 IX87_RS11835 NZ_CP009257.1 2335867 2336619 − 753 394 IX87_RS16040 NZ_CP009257.1 3210600 3212687 + 2088 394 IX87_RS06465 NZ_CP009257.1 1244622 1249127 − 4506 389 IX87_RS04525 NZ_CP009257.1 879769 880380 − 612 385 IX87_RS05530 NZ_CP009257.1 1072645 1075860 − 3216 381 IX87_RS13500 NZ_CP009257.1 2674288 2674647 − 360 381 IX87_RS02305 NZ_CP009257.1 425244 426281 − 1038 380 IX87_RS18475 NZ_CP009257.1 3699884 3702049 + 2166 380 IX87_RS11755 NZ_CP009257.1 2328932 2329288 − 357 379 IX87_RS11870 NZ_CP009257.1 2339714 2340025 − 312 376 IX87_RS16280 NZ_CP009257.1 3260688 3262844 − 2157 374 IX87_RS17790 NZ_CP009257.1 3576429 3578318 + 1890 374 IX87_RS09865 NZ_CP009257.1 1958977 1960173 − 1197 372 IX87_RS11805 NZ_CP009257.1 2333659 2334195 − 537 370 IX87_RS01750 NZ_CP009257.1 327889 329079 − 1191 365 IX87_RS13190 NZ_CP009257.1 2605354 2606253 + 900 358 IX87_RS12160 NZ_CP009257.1 2399736 2401007 − 1272 356 IX87_RS16715 NZ_CP009257.1 3350516 3352144 + 1629 352 IX87_RS13300 NZ_CP009257.1 2630383 2631150 + 768 347 IX87_RS15700 NZ_CP009257.1 3135012 3135602 + 591 347 IX87_RS13360 NZ_CP009257.1 2642488 2644470 − 1983 343 IX87_RS20715 NZ_CP009257.1 4166036 4167181 + 1146 337 IX87_RS11435 NZ_CP009257.1 2266603 2267031 + 429 335 IX87_RS21505 NZ_CP009257.1 4303748 4305118 + 1371 334 IX87_RS00440 NZ_CP009257.1 62067 63671 − 1605 330 IX87_RS17320 NZ_CP009257.1 3480635 3480973 + 339 330 IX87_RS16695 NZ_CP009257.1 3345765 3347618 + 1854 324 IX87_RS06750 NZ_CP009257.1 1311509 1313083 + 1575 320 IX87_RS14750 NZ_CP009257.1 2940826 2942109 + 1284 319 IX87_RS16955 NZ_CP009257.1 3402811 3405567 + 2757 304 IX87_RS15015 NZ_CP009257.1 2998731 2999606 + 876 300 IX87_RS03345 NZ_CP009257.1 627208 630690 + 3483 299 IX87_RS16235 NZ_CP009257.1 3250051 3253383 − 3333 295 IX87_RS12010 NZ_CP009257.1 2369134 2370084 + 951 294 IX87_RS07235 NZ_CP009257.1 1410286 1410498 − 213 289 IX87_RS08390 NZ_CP009257.1 1615750 1616997 + 1248 288 IX87_RS13195 NZ_CP009257.1 2606313 2608280 − 1968 288 IX87_RS08710 NZ_CP009257.1 1692357 1693730 − 1374 287 IX87_RS15645 NZ_CP009257.1 3119489 3119917 + 429 286 IX87_RS11795 NZ_CP009257.1 2332937 2333332 − 396 283 IX87_RS17715 NZ_CP009257.1 3563307 3563489 − 183 283 IX87_RS11735 NZ_CP009257.1 2326466 2326843 − 378 279 IX87_RS17760 NZ_CP009257.1 3569998 3571329 + 1332 279 IX87_RS17145 NZ_CP009257.1 3443650 3443844 + 195 278 IX87_RS11850 NZ_CP009257.1 2337251 2338075 − 825 275 IX87_RS11685 NZ_CP009257.1 2314954 2317008 + 2055 274 IX87_RS15925 NZ_CP009257.1 3177207 3179906 + 2700 274 IX87_RS21205 NZ_CP009257.1 4246489 4247538 + 1050 273 IX87_RS12715 NZ_CP009257.1 2516824 2517588 + 765 272 IX87_RS21315 NZ_CP009257.1 4268688 4269932 − 1245 270 IX87_RS07155 NZ_CP009257.1 1395265 1395480 + 216 266 IX87_RS06275 NZ_CP009257.1 1204344 1206950 − 2607 265 IX87_RS04520 NZ_CP009257.1 879360 879704 + 345 262 IX87_RS07845 NZ_CP009257.1 1521183 1522565 + 1383 254 IX87_RS13725 NZ_CP009257.1 2720466 2722304 + 1839 254 IX87_RS11745 NZ_CP009257.1 2327887 2328513 − 627 252 IX87_RS02665 NZ_CP009257.1 489716 490609 − 894 247 IX87_RS07455 NZ_CP009257.1 1456779 1458032 − 1254 247 IX87_RS20615 NZ_CP009257.1 4142534 4144810 − 2277 247 IX87_RS11095 NZ_CP009257.1 2202807 2204585 + 1779 246 IX87_RS15370 NZ_CP009257.1 3067271 3068719 − 1449 244 IX87_RS16880 NZ_CP009257.1 3387258 3388982 + 1725 244 IX87_RS16870 NZ_CP009257.1 3383613 3386237 − 2625 240 IX87_RS09920 NZ_CP009257.1 1972039 1973925 + 1887 239 IX87_RS11250 NZ_CP009257.1 2231341 2233242 + 1902 239 IX87_RS08950 NZ_CP009257.1 1748338 1749795 − 1458 238 IX87_RS16890 NZ_CP009257.1 3389506 3390522 + 1017 238 IX87_RS08540 NZ_CP009257.1 1651103 1653115 − 2013 237 IX87_RS13720 NZ_CP009257.1 2719089 2720453 + 1365 237 IX87_RS11170 NZ_CP009257.1 2216052 2216978 − 927 236 IX87_RS16665 NZ_CP009257.1 3336962 3338275 + 1314 236 IX87_RS07785 NZ_CP009257.1 1507059 1507934 − 876 235 IX87_RS06305 NZ_CP009257.1 1212164 1213336 + 1173 232 IX87_RS09415 NZ_CP009257.1 1839230 1841944 − 2715 232 IX87_RS16660 NZ_CP009257.1 3336255 3336860 + 606 231 IX87_RS12690 NZ_CP009257.1 2506859 2508520 − 1662 230 IX87_RS01775 NZ_CP009257.1 334318 335547 + 1230 229 IX87_RS10020 NZ_CP009257.1 1990739 1991989 + 1251 228 IX87_RS09755 NZ_CP009257.1 1920536 1921675 + 1140 227 IX87_RS18140 NZ_CP009257.1 3648577 3649527 − 951 227 IX87_RS08545 NZ_CP009257.1 1653366 1653935 − 570 225 IX87_RS15750 NZ_CP009257.1 3144288 3145460 − 1173 222 IX87_RS10030 NZ_CP009257.1 1995178 1996632 + 1455 220 IX87_RS16035 NZ_CP009257.1 3210073 3210342 + 270 218 IX87_RS08585 NZ_CP009257.1 1663238 1665856 + 2619 217 IX87_RS11770 NZ_CP009257.1 2330898 2331338 − 441 216 IX87_RS11920 NZ_CP009257.1 2349910 2352483 + 2574 216 IX87_RS16835 NZ_CP009257.1 3375467 3376198 + 732 212 IX87_RS09660 NZ_CP009257.1 1902424 1904256 + 1833 206 IX87_RS10865 NZ_CP009257.1 2152594 2153826 − 1233 206 IX87_RS13315 NZ_CP009257.1 2633562 2634899 − 1338 206 IX87_RS14635 NZ_CP009257.1 2913027 2914694 + 1668 205 IX87_RS17670 NZ_CP009257.1 3554601 3555884 − 1284 203 IX87_RS11030 NZ_CP009257.1 2186586 2187758 + 1173 202 IX87_RS13385 NZ_CP009257.1 2649792 2650967 − 1176 201 IX87_RS11820 NZ_CP009257.1 2334999 2335256 − 258 200 IX87_RS11055 NZ_CP009257.1 2192544 2194346 + 1803 199 IX87_RS17690 NZ_CP009257.1 3559580 3560296 + 717 199 IX87_RS08995 NZ_CP009257.1 1757654 1758889 + 1236 198 IX87_RS12585 NZ_CP009257.1 2488594 2488893 + 300 198 IX87_RS12435 NZ_CP009257.1 2453324 2457799 − 4476 197 IX87_RS16740 NZ_CP009257.1 3357561 3359744 + 2184 196 IX87_RS09850 NZ_CP009257.1 1955262 1956152 − 891 195 IX87_RS15720 NZ_CP009257.1 3139270 3140409 − 1140 195 IX87_RS11815 NZ_CP009257.1 2334538 2334906 − 369 194 IX87_RS15030 NZ_CP009257.1 3000458 3000994 + 537 194 IX87_RS10940 NZ_CP009257.1 2166865 2169588 − 2724 192 IX87_RS13215 NZ_CP009257.1 2610192 2611907 − 1716 192 IX87_RS14160 NZ_CP009257.1 2816591 2818351 + 1761 191 IX87_RS06350 NZ_CP009257.1 1224434 1224943 + 510 190 IX87_RS11965 NZ_CP009257.1 2359642 2360235 − 594 190 IX87_RS14455 NZ_CP009257.1 2873551 2874168 + 618 190 IX87_RS15435 NZ_CP009257.1 3081320 3082621 − 1302 190 IX87_RS00480 NZ_CP009257.1 70857 72470 − 1614 189 IX87_RS04615 NZ_CP009257.1 900663 901442 − 780 189 IX87_RS06685 NZ_CP009257.1 1297940 1298386 + 447 189 IX87_RS10790 NZ_CP009257.1 2135042 2135473 − 432 189 IX87_RS12710 NZ_CP009257.1 2513820 2516168 − 2349 188 IX87_RS15040 NZ_CP009257.1 3002663 3003532 + 870 188 IX87_RS12270 NZ_CP009257.1 2421741 2422973 + 1233 187 IX87_RS02435 NZ_CP009257.1 450849 451439 − 591 186 IX87_RS12720 NZ_CP009257.1 2517606 2519063 + 1458 186 IX87_RS13755 NZ_CP009257.1 2728221 2729633 − 1413 186 IX87_RS12420 NZ_CP009257.1 2450049 2450639 − 591 185 IX87_RS09490 NZ_CP009257.1 1856624 1859032 − 2409 184 IX87_RS08860 NZ_CP009257.1 1728937 1729419 + 483 183 IX87_RS09135 NZ_CP009257.1 1782073 1782822 − 750 183 IX87_RS11655 NZ_CP009257.1 2308487 2311087 + 2601 182 IX87_RS14375 NZ_CP009257.1 2856528 2859365 − 2838 182 IX87_RS15650 NZ_CP009257.1 3119921 3120616 + 696 182 IX87_RS08735 NZ_CP009257.1 1697312 1698382 − 1071 181 IX87_RS10935 NZ_CP009257.1 2166291 2166734 − 444 181 IX87_RS12840 NZ_CP009257.1 2535806 2536249 + 444 181 IX87_RS13745 NZ_CP009257.1 2726033 2726953 − 921 181 IX87_RS17695 NZ_CP009257.1 3560386 3561978 + 1593 181 IX87_RS08730 NZ_CP009257.1 1696205 1697299 − 1095 180 IX87_RS16655 NZ_CP009257.1 3334728 3336062 + 1335 180 IX87_RS16680 NZ_CP009257.1 3339859 3341385 − 1527 180 IX87_RS10510 NZ_CP009257.1 2078576 2080054 + 1479 179 IX87_RS11680 NZ_CP009257.1 2312388 2314820 + 2433 179 IX87_RS18070 NZ_CP009257.1 3638267 3638827 + 561 179 IX87_RS11585 NZ_CP009257.1 2297154 2298197 + 1044 178 IX87_RS13895 NZ_CP009257.1 2757634 2757996 + 363 176 IX87_RS20755 NZ_CP009257.1 4171530 4171889 − 360 175 IX87_RS16760 NZ_CP009257.1 3362171 3362602 + 432 173 IX87_RS08660 NZ_CP009257.1 1678795 1679757 − 963 172 IX87_RS15920 NZ_CP009257.1 3175712 3177196 + 1485 172 IX87_RS06380 NZ_CP009257.1 1228326 1229270 − 945 171 IX87_RS10975 NZ_CP009257.1 2175630 2176433 − 804 171 IX87_RS17200 NZ_CP009257.1 3453025 3453351 − 327 171 IX87_RS18660 NZ_CP009257.1 3739463 3741328 + 1866 171 IX87_RS13850 NZ_CP009257.1 2750180 2750782 + 603 170 IX87_RS15425 NZ_CP009257.1 3078971 3080017 + 1047 170 IX87_RS11865 NZ_CP009257.1 2339018 2339656 − 639 169 IX87_RS18655 NZ_CP009257.1 3739059 3739331 + 273 169 IX87_RS03230 NZ_CP009257.1 603458 605602 − 2145 168 IX87_RS16685 NZ_CP009257.1 3341612 3343756 − 2145 168 IX87_RS17180 NZ_CP009257.1 3447929 3450310 + 2382 168 IX87_RS21240 NZ_CP009257.1 4252339 4254843 − 2505 167 IX87_RS07335 NZ_CP009257.1 1429692 1432088 + 2397 166 IX87_RS13845 NZ_CP009257.1 2749271 2750164 + 894 166 IX87_RS20560 NZ_CP009257.1 4131167 4132804 − 1638 166 IX87_RS11800 NZ_CP009257.1 2333344 2333649 − 306 165 IX87_RS18190 NZ_CP009257.1 3656538 3657695 − 1158 165 IX87_RS09250 NZ_CP009257.1 1804710 1805273 + 564 163 IX87_RS09200 NZ_CP009257.1 1791383 1795216 − 3834 161 IX87_RS14515 NZ_CP009257.1 2885960 2886682 − 723 161 IX87_RS15660 NZ_CP009257.1 3121485 3121856 + 372 161 IX87_RS17120 NZ_CP009257.1 3438324 3440246 + 1923 161 IX87_RS10970 NZ_CP009257.1 2174737 2175633 − 897 158 IX87_RS04625 NZ_CP009257.1 901999 903318 − 1320 156 IX87_RS07245 NZ_CP009257.1 1411252 1412118 + 867 156 IX87_RS14125 NZ_CP009257.1 2808766 2811234 − 2469 156 IX87_RS15020 NZ_CP009257.1 2999691 2999936 + 246 155 IX87_RS01765 NZ_CP009257.1 332121 332495 − 375 154 IX87_RS06110 NZ_CP009257.1 1173040 1174029 + 990 154 IX87_RS22850 NZ_CP009257.1 2073253 2073426 − 174 154 IX87_RS12310 NZ_CP009257.1 2429566 2429934 − 369 154 IX87_RS12535 NZ_CP009257.1 2476050 2478605 + 2556 154 IX87_RS17755 NZ_CP009257.1 3569492 3570001 + 510 154 IX87_RS05460 NZ_CP009257.1 1057857 1059215 + 1359 152 IX87_RS14520 NZ_CP009257.1 2886874 2889060 − 2187 152 IX87_RS16435 NZ_CP009257.1 3292673 3295309 + 2637 151 IX87_RS01705 NZ_CP009257.1 317960 320992 − 3033 149 IX87_RS14765 NZ_CP009257.1 2943766 2945205 + 1440 149 IX87_RS15050 NZ_CP009257.1 3004975 3005394 + 420 149 IX87_RS08830 NZ_CP009257.1 1719220 1720476 − 1257 148 IX87_RS13320 NZ_CP009257.1 2635049 2636515 − 1467 148 IX87_RS13675 NZ_CP009257.1 2711283 2711762 − 480 148 IX87_RS17125 NZ_CP009257.1 3440252 3440803 + 552 148 IX87_RS09455 NZ_CP009257.1 1848695 1850101 − 1407 147 IX87_RS03755 NZ_CP009257.1 721468 722127 + 660 146 IX87_RS15960 NZ_CP009257.1 3183759 3186608 − 2850 146 IX87_RS04610 NZ_CP009257.1 899555 900604 + 1050 145 IX87_RS16625 NZ_CP009257.1 3326659 3327201 − 543 143 IX87_RS10500 NZ_CP009257.1 2077034 2078071 − 1038 142 IX87_RS20465 NZ_CP009257.1 4110862 4111329 − 468 141 IX87_RS02175 NZ_CP009257.1 402701 403387 − 687 140 IX87_RS16640 NZ_CP009257.1 3329080 3330777 − 1698 140 IX87_RS15710 NZ_CP009257.1 3136243 3138162 + 1920 139 IX87_RS05995 NZ_CP009257.1 1145226 1146089 − 864 138 IX87_RS08615 NZ_CP009257.1 1669829 1670977 + 1149 138 IX87_RS14975 NZ_CP009257.1 2991571 2993268 + 1698 138 IX87_RS06660 NZ_CP009257.1 1295286 1295906 + 621 137 IX87_RS03320 NZ_CP009257.1 620495 622096 + 1602 135 IX87_RS15025 NZ_CP009257.1 2999975 3000445 + 471 135 IX87_RS06965 NZ_CP009257.1 1353187 1354422 − 1236 134 IX87_RS15430 NZ_CP009257.1 3080125 3081264 − 1140 134 IX87_RS16720 NZ_CP009257.1 3352250 3353515 − 1266 134 IX87_RS18795 NZ_CP009257.1 3772739 3773848 − 1110 134 IX87_RS17060 NZ_CP009257.1 3426348 3428654 + 2307 133 IX87_RS06730 NZ_CP009257.1 1308625 1308855 + 231 132 IX87_RS08705 NZ_CP009257.1 1690822 1692354 − 1533 132 IX87_RS14295 NZ_CP009257.1 2842908 2843462 − 555 131 IX87_RS16550 NZ_CP009257.1 3312463 3312984 − 522 131 IX87_RS10930 NZ_CP009257.1 2164914 2166224 + 1311 130 IX87_RS02445 NZ_CP009257.1 452115 454103 − 1989 129 IX87_RS09640 NZ_CP009257.1 1889690 1889980 − 291 129 IX87_RS12080 NZ_CP009257.1 2383005 2385074 + 2070 129 IX87_RS13095 NZ_CP009257.1 2583282 2583908 + 627 129 IX87_RS17885 NZ_CP009257.1 3596806 3597306 + 501 129 IX87_RS02300 NZ_CP009257.1 423815 425125 + 1311 128 IX87_RS06470 NZ_CP009257.1 1249154 1251829 − 2676 127 IX87_RS16115 NZ_CP009257.1 3227602 3229314 − 1713 126 IX87_RS04995 NZ_CP009257.1 956206 957486 + 1281 125 IX87_RS14760 NZ_CP009257.1 2943286 2943603 + 318 125 IX87_RS14980 NZ_CP009257.1 2993314 2994234 − 921 124 IX87_RS17630 NZ_CP009257.1 3539555 3546541 + 6987 124 IX87_RS09875 NZ_CP009257.1 1963584 1964294 − 711 123 IX87_RS10795 NZ_CP009257.1 2135729 2137564 − 1836 123 IX87_RS14655 NZ_CP009257.1 2918661 2919875 − 1215 123 IX87_RS15160 NZ_CP009257.1 3026335 3027261 + 927 123 IX87_RS15275 NZ_CP009257.1 3050378 3050905 + 528 123 IX87_RS00435 NZ_CP009257.1 61525 62004 + 480 122 IX87_RS07295 NZ_CP009257.1 1419309 1421579 − 2271 122 IX87_RS08590 NZ_CP009257.1 1665915 1666844 − 930 122 IX87_RS10455 NZ_CP009257.1 2068632 2070062 + 1431 122 IX87_RS12380 NZ_CP009257.1 2441953 2444058 + 2106 121 IX87_RS13690 NZ_CP009257.1 2714044 2715351 + 1308 121 IX87_RS20550 NZ_CP009257.1 4128943 4130232 − 1290 121 IX87_RS04605 NZ_CP009257.1 898687 899394 + 708 120 IX87_RS09590 NZ_CP009257.1 1877109 1877492 − 384 120 IX87_RS09885 NZ_CP009257.1 1966157 1966522 − 366 120 IX87_RS13390 NZ_CP009257.1 2651132 2652394 − 1263 120 IX87_RS14100 NZ_CP009257.1 2802986 2803993 − 1008 120 IX87_RS16630 NZ_CP009257.1 3327243 3327836 − 594 119 IX87_RS04640 NZ_CP009257.1 906120 908756 + 2637 118 IX87_RS06680 NZ_CP009257.1 1297704 1297931 + 228 118 IX87_RS07400 NZ_CP009257.1 1444132 1445502 + 1371 118 IX87_RS15060 NZ_CP009257.1 3006201 3006746 − 546 118 IX87_RS10515 NZ_CP009257.1 2080054 2081523 + 1470 117 IX87_RS13085 NZ_CP009257.1 2580394 2581731 − 1338 117 IX87_RS08565 NZ_CP009257.1 1658954 1659178 − 225 116 IX87_RS08885 NZ_CP009257.1 1734034 1735878 + 1845 116 IX87_RS16810 NZ_CP009257.1 3372292 3372750 − 459 116 IX87_RS04195 NZ_CP009257.1 817667 818509 − 843 115 IX87_RS11860 NZ_CP009257.1 2338404 2339006 − 603 114 IX87_RS14755 NZ_CP009257.1 2942130 2943233 + 1104 114 IX87_RS17195 NZ_CP009257.1 3451435 3452703 − 1269 114 IX87_RS18000 NZ_CP009257.1 3624857 3625321 + 465 114 IX87_RS18630 NZ_CP009257.1 3734930 3736147 − 1218 114 IX87_RS09330 NZ_CP009257.1 1819197 1820213 − 1017 113 IX87_RS15235 NZ_CP009257.1 3040750 3042342 + 1593 113 IX87_RS17080 NZ_CP009257.1 3430924 3432357 + 1434 113 IX87_RS21350 NZ_CP009257.1 4274918 4275925 − 1008 113 IX87_RS03330 NZ_CP009257.1 622921 624912 + 1992 112 IX87_RS08795 NZ_CP009257.1 1710271 1713033 − 2763 112 IX87_RS10715 NZ_CP009257.1 2121848 2123563 + 1716 112 IX87_RS11810 NZ_CP009257.1 2334211 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69475 + 1338 105 IX87_RS17150 NZ_CP009257.1 3443856 3444215 + 360 105 IX87_RS14035 NZ_CP009257.1 2787999 2789477 − 1479 104 IX87_RS15840 NZ_CP009257.1 3162682 3163236 − 555 104 IX87_RS17275 NZ_CP009257.1 3470263 3470784 − 522 104 IX87_RS18080 NZ_CP009257.1 3639240 3640226 + 987 103 IX87_RS09625 NZ_CP009257.1 1886378 1887340 − 963 102 IX87_RS10060 NZ_CP009257.1 1999726 2002605 + 2880 102 IX87_RS02755 NZ_CP009257.1 505355 505744 + 390 101 IX87_RS09155 NZ_CP009257.1 1785453 1785869 + 417 101 IX87_RS13485 NZ_CP009257.1 2670961 2672775 − 1815 101 IX87_RS04010 NZ_CP009257.1 775754 777007 − 1254 100 IX87_RS11305 NZ_CP009257.1 2242018 2242506 + 489 100 IX87_RS15260 NZ_CP009257.1 3047644 3049323 + 1680 100 IX87_RS21125 NZ_CP009257.1 4231824 4233266 − 1443 100 IX87_RS08640 NZ_CP009257.1 1674171 1675559 + 1389 99 IX87_RS09310 NZ_CP009257.1 1815280 1816473 − 1194 99 IX87_RS11750 NZ_CP009257.1 2328526 2328912 − 387 99 IX87_RS17600 NZ_CP009257.1 3533883 3534926 + 1044 99 IX87_RS02125 NZ_CP009257.1 393451 394593 − 1143 98 IX87_RS02760 NZ_CP009257.1 505846 507063 + 1218 98 IX87_RS02805 NZ_CP009257.1 517579 518646 + 1068 98 IX87_RS09735 NZ_CP009257.1 1917851 1918501 − 651 98 IX87_RS12000 NZ_CP009257.1 2366196 2368100 − 1905 98 IX87_RS09140 NZ_CP009257.1 1783117 1783938 + 822 97 IX87_RS11575 NZ_CP009257.1 2293388 2295331 − 1944 97 IX87_RS18135 NZ_CP009257.1 3648181 3648477 − 297 96 IX87_RS00670 NZ_CP009257.1 116504 117649 + 1146 95 IX87_RS11175 NZ_CP009257.1 2217003 2219753 − 2751 95 IX87_RS13400 NZ_CP009257.1 2653312 2654238 − 927 95 IX87_RS13890 NZ_CP009257.1 2756711 2757448 + 738 95 IX87_RS14675 NZ_CP009257.1 2923401 2926007 + 2607 95 IX87_RS00485 NZ_CP009257.1 72501 73409 − 909 94 IX87_RS14625 NZ_CP009257.1 2910229 2911245 + 1017 93 IX87_RS14930 NZ_CP009257.1 2982645 2984213 + 1569 93 IX87_RS17745 NZ_CP009257.1 3566929 3567606 + 678 93 IX87_RS01680 NZ_CP009257.1 314924 315619 + 696 92 IX87_RS10010 NZ_CP009257.1 1987843 1989903 + 2061 92 IX87_RS11885 NZ_CP009257.1 2342407 2343954 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88 IX87_RS10875 NZ_CP009257.1 2155164 2156321 + 1158 88 IX87_RS14360 NZ_CP009257.1 2854844 2855386 − 543 88 IX87_RS15480 NZ_CP009257.1 3090991 3091527 − 537 88 IX87_RS16010 NZ_CP009257.1 3197970 3198476 − 507 88 IX87_RS17595 NZ_CP009257.1 3532875 3533861 + 987 88 IX87_RS20650 NZ_CP009257.1 4150285 4151832 + 1548 88 IX87_RS11790 NZ_CP009257.1 2332390 2332923 − 534 87 IX87_RS17770 NZ_CP009257.1 3574029 3575045 + 1017 87 IX87_RS04490 NZ_CP009257.1 871270 875127 − 3858 86 IX87_RS12035 NZ_CP009257.1 2374539 2376362 + 1824 86 IX87_RS17020 NZ_CP009257.1 3417125 3417478 − 354 86 IX87_RS18560 NZ_CP009257.1 3721481 3721747 − 267 86 IX87_RS07820 NZ_CP009257.1 1514528 1515940 − 1413 85 IX87_RS08715 NZ_CP009257.1 1694198 1694899 + 702 85 IX87_RS10855 NZ_CP009257.1 2148205 2149848 − 1644 85 IX87_RS16690 NZ_CP009257.1 3343800 3345002 − 1203 85 IX87_RS09840 NZ_CP009257.1 1952706 1953629 − 924 84 IX87_RS11255 NZ_CP009257.1 2233251 2234216 + 966 84 IX87_RS16485 NZ_CP009257.1 3302680 3302916 − 237 84 IX87_RS21235 NZ_CP009257.1 4251794 4252297 − 504 84 IX87_RS05000 NZ_CP009257.1 957733 957987 + 255 83 IX87_RS09675 NZ_CP009257.1 1907853 1909184 + 1332 83 IX87_RS10520 NZ_CP009257.1 2081711 2082271 + 561 83 IX87_RS11840 NZ_CP009257.1 2336621 2336950 − 330 83 IX87_RS02810 NZ_CP009257.1 518862 522425 + 3564 82 IX87_RS11060 NZ_CP009257.1 2194514 2196295 + 1782 82 IX87_RS13750 NZ_CP009257.1 2726964 2728169 − 1206 82 IX87_RS20670 NZ_CP009257.1 4155197 4158151 − 2955 82 IX87_RS03675 NZ_CP009257.1 702370 704472 + 2103 81 IX87_RS06540 NZ_CP009257.1 1266239 1267537 − 1299 81 IX87_RS07215 NZ_CP009257.1 1406727 1407800 − 1074 81 IX87_RS09365 NZ_CP009257.1 1827626 1828567 + 942 81 IX87_RS15385 NZ_CP009257.1 3071159 3072706 + 1548 81 IX87_RS15950 NZ_CP009257.1 3181583 3183394 − 1812 81 IX87_RS17285 NZ_CP009257.1 3471971 3472720 − 750 81 IX87_RS00525 NZ_CP009257.1 79790 80971 + 1182 80 IX87_RS12315 NZ_CP009257.1 2430142 2430882 − 741 80 IX87_RS12565 NZ_CP009257.1 2483874 2485706 − 1833 80 IX87_RS17175 NZ_CP009257.1 3446916 3447896 + 981 80 IX87_RS18085 NZ_CP009257.1 3640223 3640957 + 735 80 IX87_RS22975 NZ_CP009257.1 3898396 3898572 + 177 80 IX87_RS06045 NZ_CP009257.1 1155722 1156966 − 1245 79 IX87_RS09940 NZ_CP009257.1 1975763 1976947 + 1185 79 IX87_RS09975 NZ_CP009257.1 1983125 1983913 − 789 79 IX87_RS13620 NZ_CP009257.1 2699364 2700518 + 1155 79 IX87_RS14015 NZ_CP009257.1 2783359 2785188 − 1830 79 IX87_RS17190 NZ_CP009257.1 3450774 3451019 − 246 79 IX87_RS21225 NZ_CP009257.1 4250227 4250712 − 486 79 IX87_RS01625 NZ_CP009257.1 302849 303916 − 1068 78 IX87_RS09510 NZ_CP009257.1 1862092 1862697 + 606 78 IX87_RS02660 NZ_CP009257.1 488779 489621 − 843 77 IX87_RS07825 NZ_CP009257.1 1516122 1517150 + 1029 77 IX87_RS12415 NZ_CP009257.1 2448945 2450027 − 1083 77 IX87_RS00620 NZ_CP009257.1 101838 103385 + 1548 76 IX87_RS06670 NZ_CP009257.1 1296246 1297124 + 879 76 IX87_RS09205 NZ_CP009257.1 1795526 1796866 + 1341 76 IX87_RS13105 NZ_CP009257.1 2585008 2586456 − 1449 76 IX87_RS17210 NZ_CP009257.1 3455170 3455991 + 822 76 IX87_RS20565 NZ_CP009257.1 4133028 4133516 + 489 76 IX87_RS02765 NZ_CP009257.1 507091 509754 + 2664 75 IX87_RS17040 NZ_CP009257.1 3420181 3422988 − 2808 75 IX87_RS17775 NZ_CP009257.1 3575064 3575606 + 543 75 IX87_RS21215 NZ_CP009257.1 4248502 4249386 + 885 75 IX87_RS05445 NZ_CP009257.1 1054064 1054942 − 879 74 IX87_RS05620 NZ_CP009257.1 1091422 1091982 + 561 74 IX87_RS08700 NZ_CP009257.1 1689115 1690545 − 1431 74 IX87_RS08845 NZ_CP009257.1 1724221 1725924 − 1704 74 IX87_RS21265 NZ_CP009257.1 4259038 4259592 − 555 74 IX87_RS02795 NZ_CP009257.1 513691 515121 + 1431 73 IX87_RS13405 NZ_CP009257.1 2654276 2655724 − 1449 73 IX87_RS00535 NZ_CP009257.1 81977 82885 + 909 72 IX87_RS02395 NZ_CP009257.1 441109 442599 + 1491 72 IX87_RS05555 NZ_CP009257.1 1080881 1081588 − 708 72 IX87_RS09970 NZ_CP009257.1 1981735 1983006 − 1272 72 IX87_RS10470 NZ_CP009257.1 2071838 2073223 + 1386 72 IX87_RS12820 NZ_CP009257.1 2532619 2533308 + 690 72 IX87_RS17340 NZ_CP009257.1 3483415 3484704 + 1290 72 IX87_RS07750 NZ_CP009257.1 1501495 1502496 + 1002 71 IX87_RS13310 NZ_CP009257.1 2632895 2633560 − 666 71 IX87_RS13695 NZ_CP009257.1 2715590 2716711 + 1122 71 IX87_RS08750 NZ_CP009257.1 1700458 1703295 − 2838 70 IX87_RS17465 NZ_CP009257.1 3509353 3510573 + 1221 70 IX87_RS02625 NZ_CP009257.1 482924 483484 + 561 69 IX87_RS03315 NZ_CP009257.1 619298 620470 + 1173 69 IX87_RS07830 NZ_CP009257.1 1517434 1519899 + 2466 69 IX87_RS08690 NZ_CP009257.1 1686702 1688423 − 1722 69 IX87_RS10155 NZ_CP009257.1 2022241 2023596 + 1356 69 IX87_RS10945 NZ_CP009257.1 2169996 2170637 + 642 69 IX87_RS12265 NZ_CP009257.1 2419952 2421361 − 1410 69 IX87_RS13395 NZ_CP009257.1 2652455 2653309 − 855 69 IX87_RS14525 NZ_CP009257.1 2889080 2889508 − 429 69 IX87_RS18075 NZ_CP009257.1 3638902 3639087 + 186 69 IX87_RS03740 NZ_CP009257.1 719517 719951 − 435 68 IX87_RS07755 NZ_CP009257.1 1502835 1503404 + 570 68 IX87_RS09350 NZ_CP009257.1 1824482 1825717 − 1236 68 IX87_RS11780 NZ_CP009257.1 2331525 2332022 − 498 68 IX87_RS11605 NZ_CP009257.1 2300717 2301430 + 714 67 IX87_RS14440 NZ_CP009257.1 2871148 2871894 − 747 67 IX87_RS00495 NZ_CP009257.1 75422 76984 − 1563 66 IX87_RS01770 NZ_CP009257.1 332696 333967 − 1272 66 IX87_RS02295 NZ_CP009257.1 421374 423815 + 2442 66 IX87_RS12375 NZ_CP009257.1 2441466 2441744 + 279 66 IX87_RS13225 NZ_CP009257.1 2612425 2615922 + 3498 66 IX87_RS13260 NZ_CP009257.1 2621249 2623198 − 1950 66 IX87_RS15455 NZ_CP009257.1 3085152 3087005 + 1854 66 IX87_RS15470 NZ_CP009257.1 3088809 3090005 + 1197 66 IX87_RS17230 NZ_CP009257.1 3458791 3461562 − 2772 66 IX87_RS18925 NZ_CP009257.1 3796144 3797355 + 1212 66 IX87_RS03335 NZ_CP009257.1 624909 625814 + 906 65 IX87_RS12560 NZ_CP009257.1 2482371 2483870 − 1500 65 IX87_RS17100 NZ_CP009257.1 3434566 3435417 + 852 65 IX87_RS19190 NZ_CP009257.1 3849925 3851097 − 1173 65 IX87_RS10760 NZ_CP009257.1 2129379 2130488 − 1110 64 IX87_RS12020 NZ_CP009257.1 2371092 2373395 − 2304 64 IX87_RS12395 NZ_CP009257.1 2445211 2445675 + 465 64 IX87_RS16105 NZ_CP009257.1 3226225 3227034 − 810 64 IX87_RS16285 NZ_CP009257.1 3263359 3265653 − 2295 64 IX87_RS09045 NZ_CP009257.1 1764296 1765318 − 1023 63 IX87_RS09785 NZ_CP009257.1 1927221 1927937 + 717 63 IX87_RS11560 NZ_CP009257.1 2291062 2291307 − 246 63 IX87_RS12130 NZ_CP009257.1 2392685 2393446 + 762 63 IX87_RS12215 NZ_CP009257.1 2410904 2411479 + 576 63 IX87_RS12845 NZ_CP009257.1 2536305 2538182 − 1878 63 IX87_RS14645 NZ_CP009257.1 2915463 2916614 + 1152 63 IX87_RS15530 NZ_CP009257.1 3100915 3102348 − 1434 63 IX87_RS17880 NZ_CP009257.1 3594456 3596519 − 2064 63 IX87_RS17905 NZ_CP009257.1 3600653 3601246 + 594 63 IX87_RS17990 NZ_CP009257.1 3621435 3622472 + 1038 63 IX87_RS19455 NZ_CP009257.1 3905950 3907644 + 1695 63 IX87_RS02195 NZ_CP009257.1 405539 406252 − 714 62 IX87_RS02450 NZ_CP009257.1 454627 455793 + 1167 62 IX87_RS06220 NZ_CP009257.1 1193517 1194752 − 1236 62 IX87_RS09925 NZ_CP009257.1 1974023 1974310 + 288 62 IX87_RS11180 NZ_CP009257.1 2219822 2221090 − 1269 62 IX87_RS16475 NZ_CP009257.1 3300654 3302363 − 1710 62 IX87_RS16930 NZ_CP009257.1 3397274 3398137 + 864 62 IX87_RS18865 NZ_CP009257.1 3787983 3788573 + 591 62 IX87_RS02500 NZ_CP009257.1 463106 464107 + 1002 61 IX87_RS11845 NZ_CP009257.1 2336962 2337237 − 276 61 IX87_RS13180 NZ_CP009257.1 2599787 2602621 + 2835 61 IX87_RS13490 NZ_CP009257.1 2672804 2673571 − 768 61 IX87_RS16865 NZ_CP009257.1 3383076 3383585 − 510 61 IX87_RS17950 NZ_CP009257.1 3612346 3613755 + 1410 61 IX87_RS06625 NZ_CP009257.1 1283074 1284903 − 1830 60 IX87_RS08930 NZ_CP009257.1 1744251 1745384 − 1134 60 IX87_RS10710 NZ_CP009257.1 2118691 2121789 + 3099 60 IX87_RS12075 NZ_CP009257.1 2382028 2383005 + 978 60 IX87_RS13680 NZ_CP009257.1 2712016 2712351 − 336 60 IX87_RS15640 NZ_CP009257.1 3118847 3119380 + 534 60 IX87_RS15965 NZ_CP009257.1 3186923 3188305 − 1383 60 IX87_RS16100 NZ_CP009257.1 3224669 3226228 − 1560 60 IX87_RS16390 NZ_CP009257.1 3283775 3285061 + 1287 60 IX87_RS16820 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NZ_CP009257.1 3891187 3893262 + 2076 55 IX87_RS00450 NZ_CP009257.1 65373 66698 + 1326 54 IX87_RS04485 NZ_CP009257.1 870069 871175 − 1107 54 IX87_RS08310 NZ_CP009257.1 1594313 1597078 − 2766 54 IX87_RS08935 NZ_CP009257.1 1745400 1746620 − 1221 54 IX87_RS09150 NZ_CP009257.1 1784756 1785439 + 684 54 IX87_RS12550 NZ_CP009257.1 2479843 2480961 − 1119 54 IX87_RS12760 NZ_CP009257.1 2523736 2524284 + 549 54 IX87_RS13410 NZ_CP009257.1 2655736 2656833 − 1098 54 IX87_RS13855 NZ_CP009257.1 2750820 2751539 + 720 54 IX87_RS17090 NZ_CP009257.1 3432882 3433691 + 810 54 IX87_RS17110 NZ_CP009257.1 3435686 3436222 + 537 54 IX87_RS17785 NZ_CP009257.1 3576124 3576432 + 309 54 IX87_RS02190 NZ_CP009257.1 404418 405542 − 1125 53 IX87_RS04000 NZ_CP009257.1 774137 774943 − 807 53 IX87_RS06090 NZ_CP009257.1 1168229 1169620 − 1392 53 IX87_RS02770 NZ_CP009257.1 509780 510949 + 1170 52 IX87_RS11455 NZ_CP009257.1 2268707 2269363 + 657 52 IX87_RS12145 NZ_CP009257.1 2395858 2397327 − 1470 52 IX87_RS14395 NZ_CP009257.1 2862452 2863072 − 621 52 IX87_RS14510 NZ_CP009257.1 2885213 2885920 − 708 52 IX87_RS16735 NZ_CP009257.1 3356349 3357368 − 1020 52 IX87_RS17235 NZ_CP009257.1 3461717 3464524 + 2808 52 IX87_RS21245 NZ_CP009257.1 4254902 4256257 − 1356 52 IX87_RS00575 NZ_CP009257.1 91348 91986 − 639 51 IX87_RS02650 NZ_CP009257.1 487342 488085 − 744 51 IX87_RS03305 NZ_CP009257.1 616730 618424 − 1695 51 IX87_RS04005 NZ_CP009257.1 774955 775719 − 765 51 IX87_RS04230 NZ_CP009257.1 825773 826321 − 549 51 IX87_RS10745 NZ_CP009257.1 2126638 2127348 + 711 51 IX87_RS12155 NZ_CP009257.1 2398377 2399591 − 1215 51 IX87_RS14640 NZ_CP009257.1 2914714 2915466 + 753 51 IX87_RS16785 NZ_CP009257.1 3366689 3367981 + 1293 51 IX87_RS21495 NZ_CP009257.1 4302839 4303294 + 456 51 IX87_RS02200 NZ_CP009257.1 406303 406899 − 597 50 IX87_RS07160 NZ_CP009257.1 1395507 1395953 + 447 50 IX87_RS07185 NZ_CP009257.1 1401319 1402860 − 1542 50 IX87_RS11960 NZ_CP009257.1 2359343 2359630 − 288 50 IX87_RS11975 NZ_CP009257.1 2360990 2361766 − 777 50 IX87_RS13370 NZ_CP009257.1 2647441 2648133 − 693 50 IX87_RS17095 NZ_CP009257.1 3433695 3434543 + 849 50 IX87_RS18115 NZ_CP009257.1 3644670 3646451 + 1782 50 IX87_RS19200 NZ_CP009257.1 3852689 3853330 − 642 50 IX87_RS07315 NZ_CP009257.1 1425256 1426614 − 1359 49 IX87_RS12165 NZ_CP009257.1 2402043 2403476 − 1434 49 IX87_RS12205 NZ_CP009257.1 2408903 2409547 + 645 49 IX87_RS14770 NZ_CP009257.1 2945576 2947006 + 1431 49 IX87_RS17910 NZ_CP009257.1 3601361 3601930 + 570 49 IX87_RS20800 NZ_CP009257.1 4178264 4179565 + 1302 49 IX87_RS01670 NZ_CP009257.1 312786 313712 + 927 48 IX87_RS02655 NZ_CP009257.1 488099 488776 − 678 48 IX87_RS07385 NZ_CP009257.1 1440676 1441455 + 780 48 IX87_RS07850 NZ_CP009257.1 1522637 1523473 + 837 48 IX87_RS08375 NZ_CP009257.1 1612960 1613430 − 471 48 IX87_RS08610 NZ_CP009257.1 1669280 1669702 + 423 48 IX87_RS14965 NZ_CP009257.1 2988514 2989140 − 627 48 IX87_RS18590 NZ_CP009257.1 3725600 3729061 + 3462 48 IX87_RS19165 NZ_CP009257.1 3844727 3846145 − 1419 48 IX87_RS07170 NZ_CP009257.1 1397617 1398582 − 966 47 IX87_RS12140 NZ_CP009257.1 2394497 2395840 − 1344 47 IX87_RS15600 NZ_CP009257.1 3114826 3116319 + 1494 47 IX87_RS16815 NZ_CP009257.1 3372778 3373035 − 258 47 IX87_RS16885 NZ_CP009257.1 3388982 3389473 + 492 47 IX87_RS17130 NZ_CP009257.1 3441010 3441630 + 621 47 IX87_RS01710 NZ_CP009257.1 321262 322209 + 948 46 IX87_RS01720 NZ_CP009257.1 323079 323894 + 816 46 IX87_RS02160 NZ_CP009257.1 400074 400439 − 366 46 IX87_RS02315 NZ_CP009257.1 426770 427957 − 1188 46 IX87_RS02970 NZ_CP009257.1 555280 556284 + 1005 46 IX87_RS10015 NZ_CP009257.1 1990088 1990714 + 627 46 IX87_RS10505 NZ_CP009257.1 2078208 2078522 + 315 46 IX87_RS11330 NZ_CP009257.1 2245026 2245361 + 336 46 IX87_RS11545 NZ_CP009257.1 2288838 2289695 − 858 46 IX87_RS12150 NZ_CP009257.1 2397327 2398358 − 1032 46 IX87_RS12695 NZ_CP009257.1 2508819 2510096 + 1278 46 IX87_RS12870 NZ_CP009257.1 2540172 2540987 + 816 46 IX87_RS16355 NZ_CP009257.1 3274949 3275959 + 1011 46 IX87_RS18600 NZ_CP009257.1 3729749 3731218 + 1470 46 IX87_RS20780 NZ_CP009257.1 4175208 4175549 + 342 46 IX87_RS09240 NZ_CP009257.1 1801905 1803308 + 1404 45 IX87_RS09265 NZ_CP009257.1 1806727 1807503 + 777 45 IX87_RS10965 NZ_CP009257.1 2173454 2174740 − 1287 45 IX87_RS11580 NZ_CP009257.1 2295620 2297071 + 1452 45 IX87_RS11620 NZ_CP009257.1 2303012 2304259 + 1248 45 IX87_RS11830 NZ_CP009257.1 2335450 2335863 − 414 45 IX87_RS15585 NZ_CP009257.1 3111043 3113313 + 2271 45 IX87_RS16135 NZ_CP009257.1 3232226 3233242 + 1017 45 IX87_RS17410 NZ_CP009257.1 3499428 3500879 + 1452 45 IX87_RS00845 NZ_CP009257.1 151849 153471 − 1623 44 IX87_RS04170 NZ_CP009257.1 811981 814626 + 2646 44 IX87_RS06645 NZ_CP009257.1 1291162 1291917 + 756 44 IX87_RS07870 NZ_CP009257.1 1529796 1531034 + 1239 44 IX87_RS08765 NZ_CP009257.1 1704977 1706275 − 1299 44 IX87_RS09690 NZ_CP009257.1 1910652 1911500 − 849 44 IX87_RS10150 NZ_CP009257.1 2020674 2021861 − 1188 44 IX87_RS12700 NZ_CP009257.1 2510370 2511260 + 891 44 IX87_RS13705 NZ_CP009257.1 2717197 2717646 + 450 44 IX87_RS14040 NZ_CP009257.1 2790073 2790798 + 726 44 IX87_RS16645 NZ_CP009257.1 3331236 3331928 − 693 44 IX87_RS17985 NZ_CP009257.1 3617984 3621433 + 3450 44 IX87_RS19460 NZ_CP009257.1 3907874 3908983 + 1110 44 IX87_RS06065 NZ_CP009257.1 1161384 1163564 − 2181 43 IX87_RS07935 NZ_CP009257.1 1540440 1541981 + 1542 43 IX87_RS09020 NZ_CP009257.1 1760911 1761669 − 759 43 IX87_RS09325 NZ_CP009257.1 1818369 1819178 − 810 43 IX87_RS12685 NZ_CP009257.1 2506472 2506816 + 345 43 IX87_RS13600 NZ_CP009257.1 2695104 2696681 − 1578 43 IX87_RS14075 NZ_CP009257.1 2797731 2798963 − 1233 43 IX87_RS15360 NZ_CP009257.1 3066194 3066832 − 639 43 IX87_RS15705 NZ_CP009257.1 3135787 3136140 + 354 43 IX87_RS18735 NZ_CP009257.1 3759445 3761763 + 2319 43 IX87_RS00545 NZ_CP009257.1 83744 85822 − 2079 42 IX87_RS00630 NZ_CP009257.1 104927 106456 − 1530 42 IX87_RS02635 NZ_CP009257.1 484378 485127 + 750 42 IX87_RS04185 NZ_CP009257.1 816071 816742 + 672 42 IX87_RS04250 NZ_CP009257.1 828625 830046 + 1422 42 IX87_RS04570 NZ_CP009257.1 890142 892367 + 2226 42 IX87_RS06155 NZ_CP009257.1 1182334 1182777 + 444 42 IX87_RS06725 NZ_CP009257.1 1306512 1308392 − 1881 42 IX87_RS09830 NZ_CP009257.1 1950037 1951539 − 1503 42 IX87_RS09835 NZ_CP009257.1 1951777 1952676 − 900 42 IX87_RS10600 NZ_CP009257.1 2099104 2099679 + 576 42 IX87_RS10830 NZ_CP009257.1 2144880 2145395 + 516 42 IX87_RS11540 NZ_CP009257.1 2287963 2288796 − 834 42 IX87_RS11890 NZ_CP009257.1 2344100 2344864 + 765 42 IX87_RS14450 NZ_CP009257.1 2872658 2873371 − 714 42 IX87_RS14950 NZ_CP009257.1 2986338 2987285 + 948 42 IX87_RS15375 NZ_CP009257.1 3068863 3069963 + 1101 42 IX87_RS16945 NZ_CP009257.1 3400933 3401874 + 942 42 IX87_RS18515 NZ_CP009257.1 3710575 3712398 + 1824 42 IX87_RS20680 NZ_CP009257.1 4160723 4161727 + 1005 42 IX87_RS21230 NZ_CP009257.1 4250719 4251789 − 1071 42 IX87_RS21345 NZ_CP009257.1 4273409 4274803 − 1395 42 IX87_RS21510 NZ_CP009257.1 4305170 4305673 − 504 42 IX87_RS00855 NZ_CP009257.1 154353 155825 + 1473 41 IX87_RS02830 NZ_CP009257.1 525249 527255 + 2007 41 IX87_RS04560 NZ_CP009257.1 888440 889456 − 1017 41 IX87_RS06690 NZ_CP009257.1 1298587 1300032 + 1446 41 IX87_RS08555 NZ_CP009257.1 1655041 1656786 + 1746 41 IX87_RS09845 NZ_CP009257.1 1953837 1954850 + 1014 41 IX87_RS10460 NZ_CP009257.1 2070130 2070747 − 618 41 IX87_RS15255 NZ_CP009257.1 3045127 3047346 + 2220 41 IX87_RS07860 NZ_CP009257.1 1524349 1527197 + 2849 40 IX87_RS07875 NZ_CP009257.1 1531084 1532259 − 1176 40 IX87_RS09890 NZ_CP009257.1 1966522 1966923 − 402 40 IX87_RS09945 NZ_CP009257.1 1977213 1978598 + 1386 40 IX87_RS12430 NZ_CP009257.1 2451833 2453254 − 1422 40 IX87_RS12640 NZ_CP009257.1 2496176 2497132 − 957 40 IX87_RS13885 NZ_CP009257.1 2756381 2756539 + 159 40 IX87_RS13920 NZ_CP009257.1 2760640 2761668 + 1029 40 IX87_RS14185 NZ_CP009257.1 2822004 2822255 − 252 40 IX87_RS14710 NZ_CP009257.1 2932967 2933668 − 702 40 IX87_RS16380 NZ_CP009257.1 3280656 3281774 − 1119 40 IX87_RS16830 NZ_CP009257.1 3374745 3375311 + 567 40 IX87_RS17815 NZ_CP009257.1 3582583 3583470 − 888 40 IX87_RS18535 NZ_CP009257.1 3716546 3718276 + 1731 40 IX87_RS21200 NZ_CP009257.1 4245903 4246343 + 441 40 IX87_RS00530 NZ_CP009257.1 81071 81970 + 900 39 IX87_RS01555 NZ_CP009257.1 288317 289330 + 1014 39 IX87_RS02790 NZ_CP009257.1 513031 513450 − 420 39 IX87_RS06410 NZ_CP009257.1 1233674 1234378 − 705 39 IX87_RS06775 NZ_CP009257.1 1317562 1318293 + 732 39 IX87_RS09230 NZ_CP009257.1 1800751 1801449 + 699 39 IX87_RS09335 NZ_CP009257.1 1820350 1821333 + 984 39 IX87_RS12675 NZ_CP009257.1 2504854 2505252 − 399 39 IX87_RS14140 NZ_CP009257.1 2813630 2815027 − 1398 39 IX87_RS15345 NZ_CP009257.1 3063792 3065084 + 1293 39 IX87_RS16230 NZ_CP009257.1 3248017 3249858 − 1842 39 IX87_RS16290 NZ_CP009257.1 3265738 3266223 − 486 39 IX87_RS16470 NZ_CP009257.1 3300338 3300616 + 279 39 IX87_RS16520 NZ_CP009257.1 3307019 3308443 − 1425 39 IX87_RS01675 NZ_CP009257.1 313729 314775 + 1047 38 IX87_RS05610 NZ_CP009257.1 1089335 1090657 − 1323 38 IX87_RS06630 NZ_CP009257.1 1284903 1287341 − 2439 38 IX87_RS07195 NZ_CP009257.1 1403480 1404484 − 1005 38 IX87_RS07285 NZ_CP009257.1 1417166 1418626 − 1461 38 IX87_RS07740 NZ_CP009257.1 1499554 1500204 + 651 38 IX87_RS09445 NZ_CP009257.1 1847057 1848307 − 1251 38 IX87_RS09965 NZ_CP009257.1 1980294 1981667 − 1374 38 IX87_RS10840 NZ_CP009257.1 2146806 2147249 + 444 38 IX87_RS11000 NZ_CP009257.1 2180287 2181516 − 1230 38 IX87_RS11400 NZ_CP009257.1 2260767 2262101 + 1335 38 IX87_RS13295 NZ_CP009257.1; 2628895; 2629917; −; − 1095 38 NZ_CP009257.1 2629919 2629990 IX87_RS13955 NZ_CP009257.1 2767310 2768131 − 822 38 IX87_RS14265 NZ_CP009257.1 2834833 2835954 + 1122 38 IX87_RS14460 NZ_CP009257.1 2874246 2874893 − 648 38 IX87_RS16065 NZ_CP009257.1 3216427 3217302 − 876 38 IX87_RS16070 NZ_CP009257.1 3217468 3219309 − 1842 38 IX87_RS18610 NZ_CP009257.1 3731624 3733483 − 1860 38 IX87_RS21280 NZ_CP009257.1 4262143 4263252 + 1110 38 IX87_RS00560 NZ_CP009257.1 87492 89951 − 2460 37 IX87_RS04365 NZ_CP009257.1 845881 846105 − 225 37 IX87_RS08535 NZ_CP009257.1 1650798 1651100 − 303 37 IX87_RS09065 NZ_CP009257.1 1767291 1769108 − 1818 37 IX87_RS10415 NZ_CP009257.1 2059846 2060721 − 876 37 IX87_RS13545 NZ_CP009257.1 2682063 2683946 − 1884 37 IX87_RS19385 NZ_CP009257.1 3893636 3894547 + 912 37 IX87_RS02680 NZ_CP009257.1 492032 492796 − 765 36 IX87_RS02735 NZ_CP009257.1 503163 503498 + 336 36 IX87_RS03245 NZ_CP009257.1 608147 608368 + 222 36 IX87_RS04245 NZ_CP009257.1 827434 828411 − 978 36 IX87_RS07205 NZ_CP009257.1 1405053 1406192 − 1140 36 IX87_RS08900 NZ_CP009257.1 1737908 1739044 − 1137 36 IX87_RS12135 NZ_CP009257.1 2393510 2394484 − 975 36 IX87_RS12770 NZ_CP009257.1 2525107 2525838 + 732 36 IX87_RS13665 NZ_CP009257.1 2709417 2710631 − 1215 36 IX87_RS14620 NZ_CP009257.1 2908566 2910236 + 1671 36 IX87_RS15465 NZ_CP009257.1 3087438 3088784 + 1347 36 IX87_RS15635 NZ_CP009257.1 3118399 3118839 + 441 36 IX87_RS17025 NZ_CP009257.1 3417608 3418402 − 795 36 IX87_RS17470 NZ_CP009257.1 3510720 3511784 + 1065 36 IX87_RS18010 NZ_CP009257.1 3626878 3628272 − 1395 36 IX87_RS19005 NZ_CP009257.1 3808773 3809864 + 1092 36 IX87_RS20740 NZ_CP009257.1 4169103 4169699 − 597 36 IX87_RS02270 NZ_CP009257.1 417143 418030 − 888 35 IX87_RS06780 NZ_CP009257.1 1318650 1318853 + 204 35 IX87_RS11900 NZ_CP009257.1 2345496 2346272 + 777 35 IX87_RS12555 NZ_CP009257.1 2480962 2482362 − 1401 35 IX87_RS13640 NZ_CP009257.1 2704006 2704716 + 711 35 IX87_RS14150 NZ_CP009257.1 2815862 2816254 + 393 35 IX87_RS15995 NZ_CP009257.1 3194518 3195465 − 948 35 IX87_RS16365 NZ_CP009257.1 3276791 3277762 − 972 35 IX87_RS17890 NZ_CP009257.1 3597452 3598681 + 1230 35 IX87_RS18635 NZ_CP009257.1 3736149 3736622 − 474 35 IX87_RS20770 NZ_CP009257.1 4173290 4173721 + 432 35 IX87_RS20835 NZ_CP009257.1 4186200 4187918 + 1719 35 IX87_RS01535 NZ_CP009257.1 282437 284401 − 1965 34 IX87_RS02165 NZ_CP009257.1 400464 400766 − 303 34 IX87_RS02345 NZ_CP009257.1 432377 433579 + 1203 34 IX87_RS04305 NZ_CP009257.1 838139 838954 − 816 34 IX87_RS04630 NZ_CP009257.1 903383 904549 − 1167 34 IX87_RS08780 NZ_CP009257.1 1707595 1709058 + 1464 34 IX87_RS09375 NZ_CP009257.1 1830264 1831751 + 1488 34 IX87_RS10465 NZ_CP009257.1 2070902 2071666 + 765 34 IX87_RS10575 NZ_CP009257.1 2092143 2093618 − 1476 34 IX87_RS11390 NZ_CP009257.1 2258128 2259753 + 1626 34 IX87_RS11855 NZ_CP009257.1 2338087 2338407 − 321 34 IX87_RS11950 NZ_CP009257.1 2357521 2358102 − 582 34 IX87_RS11990 NZ_CP009257.1 2362985 2364832 − 1848 34 IX87_RS12180 NZ_CP009257.1 2404776 2406053 − 1278 34 IX87_RS15000 NZ_CP009257.1 2996594 2997058 − 465 34 IX87_RS15800 NZ_CP009257.1 3155209 3155796 + 588 34 IX87_RS15970 NZ_CP009257.1 3188329 3189831 − 1503 34 IX87_RS16180 NZ_CP009257.1 3238496 3239794 − 1299 34 IX87_RS16765 NZ_CP009257.1 3362725 3363957 + 1233 34 IX87_RS16825 NZ_CP009257.1 3373561 3374619 − 1059 34 IX87_RS16935 NZ_CP009257.1 3398341 3399933 + 1593 34 IX87_RS18060 NZ_CP009257.1 3636801 3637418 − 618 34 IX87_RS19195 NZ_CP009257.1 3851163 3852572 − 1410 34 IX87_RS21250 NZ_CP009257.1 4256259 4257455 − 1197 34 IX87_RS00800 NZ_CP009257.1 141775 143769 − 1995 33 IX87_RS01615 NZ_CP009257.1 302073 302471 + 399 33 IX87_RS01660 NZ_CP009257.1 309655 311694 − 2040 33 IX87_RS03860 NZ_CP009257.1 746078 746581 − 504 33 IX87_RS04235 NZ_CP009257.1 826305 826853 − 549 33 IX87_RS05395 NZ_CP009257.1 1044136 1047255 − 3120 33 IX87_RS06050 NZ_CP009257.1 1157192 1158349 + 1158 33 IX87_RS08980 NZ_CP009257.1 1754836 1755627 + 792 33 IX87_RS11635 NZ_CP009257.1 2305603 2306244 − 642 33 IX87_RS12115 NZ_CP009257.1 2389861 2390292 + 432 33 IX87_RS13415 NZ_CP009257.1 2657071 2658015 − 945 33 IX87_RS13610 NZ_CP009257.1 2697449 2698012 + 564 33 IX87_RS15845 NZ_CP009257.1 3163363 3165030 − 1668 33 IX87_RS16335 NZ_CP009257.1 3272335 3273414 + 1080 33 IX87_RS16775 NZ_CP009257.1 3364764 3365555 + 792 33 IX87_RS17205 NZ_CP009257.1 3453631 3455151 + 1521 33 IX87_RS18975 NZ_CP009257.1 3803509 3803814 + 306 33 IX87_RS18985 NZ_CP009257.1 3804223 3805074 + 852 33 IX87_RS19205 NZ_CP009257.1 3853332 3854036 − 705 33 IX87_RS20765 NZ_CP009257.1 4172817 4173149 + 333 33 IX87_RS00860 NZ_CP009257.1 155921 157579 + 1659 32 IX87_RS02420 NZ_CP009257.1 449014 449244 + 231 32 IX87_RS03175 NZ_CP009257.1 591047 591331 − 285 32 IX87_RS03990 NZ_CP009257.1 770803 772521 − 1719 32 IX87_RS04190 NZ_CP009257.1 816882 817550 + 669 32 IX87_RS04540 NZ_CP009257.1 884059 884685 + 627 32 IX87_RS06825 NZ_CP009257.1 1327527 1329194 − 1668 32 IX87_RS07350 NZ_CP009257.1 1433718 1433888 + 171 32 IX87_RS09080 NZ_CP009257.1 1771463 1773106 + 1644 32 IX87_RS09165 NZ_CP009257.1 1786664 1787125 + 462 32 IX87_RS10740 NZ_CP009257.1 2125770 2126492 + 723 32 IX87_RS10750 NZ_CP009257.1 2127531 2128355 + 825 32 IX87_RS11570 NZ_CP009257.1 2292668 2293330 − 663 32 IX87_RS11610 NZ_CP009257.1 2301503 2302078 + 576 32 IX87_RS12285 NZ_CP009257.1 2424915 2425358 − 444 32 IX87_RS13270 NZ_CP009257.1 2624181 2625161 + 981 32 IX87_RS13460 NZ_CP009257.1 2666433 2667257 + 825 32 IX87_RS13590 NZ_CP009257.1 2691026 2694409 − 3384 32 IX87_RS14380 NZ_CP009257.1 2859427 2860428 − 1002 32 IX87_RS15200 NZ_CP009257.1 3034747 3035100 − 354 32 IX87_RS15760 NZ_CP009257.1 3148198 3149112 + 915 32 IX87_RS16925 NZ_CP009257.1 3396371 3396943 − 573 32 IX87_RS17605 NZ_CP009257.1 3535112 3535603 + 492 32 IX87_RS17945 NZ_CP009257.1 3611396 3612205 − 810 32 IX87_RS18760 NZ_CP009257.1 3765132 3767234 + 2103 32 IX87_RS18960 NZ_CP009257.1 3802092 3802358 + 267 32 IX87_RS02785 NZ_CP009257.1 512549 513034 − 486 31 IX87_RS06365 NZ_CP009257.1 1226044 1226697 + 654 31 IX87_RS13685 NZ_CP009257.1 2712761 2713984 − 1224 31 IX87_RS14445 NZ_CP009257.1 2871960 2872661 − 702 31 IX87_RS15010 NZ_CP009257.1 2998228 2998626 + 399 31 IX87_RS15990 NZ_CP009257.1 3193838 3194506 − 669 31 IX87_RS17055 NZ_CP009257.1 3424926 3426317 + 1392 31 IX87_RS17220 NZ_CP009257.1 3457303 3458139 + 837 31 IX87_RS18065 NZ_CP009257.1 3637508 3638080 − 573 31 IX87_RS18935 NZ_CP009257.1 3798035 3798364 + 330 31 IX87_RS21275 NZ_CP009257.1 4260458 4261801 − 1344 31 IX87_RS05025 NZ_CP009257.1 961029 962348 − 1320 30 IX87_RS08970 NZ_CP009257.1 1751954 1752541 − 588 30 IX87_RS09260 NZ_CP009257.1 1805699 1806670 + 972 30 IX87_RS10480 NZ_CP009257.1 2073566 2075020 − 1455 30 IX87_RS12705 NZ_CP009257.1 2511328 2513517 − 2190 30 IX87_RS14240 NZ_CP009257.1 2830830 2832080 + 1251 30 IX87_RS15380 NZ_CP009257.1 3069963 3071033 + 1071 30 IX87_RS15475 NZ_CP009257.1 3090056 3090988 − 933 30 IX87_RS15590 NZ_CP009257.1 3113354 3113983 + 630 30 IX87_RS15850 NZ_CP009257.1 3165183 3166454 + 1272 30 IX87_RS16020 NZ_CP009257.1 3202305 3205985 + 3681 30 IX87_RS16445 NZ_CP009257.1 3296293 3296865 + 573 30 IX87_RS16450 NZ_CP009257.1 3296982 3298961 + 1980 30 IX87_RS16840 NZ_CP009257.1 3376305 3377138 + 834 30 IX87_RS17170 NZ_CP009257.1 3445757 3446758 − 1002 30 IX87_RS18595 NZ_CP009257.1 3729262 3729696 + 435 30 IX87_RS18620 NZ_CP009257.1 3734126 3734446 − 321 30 IX87_RS21115 NZ_CP009257.1 4229107 4231200 + 2094 30 IX87_RS03080 NZ_CP009257.1 574567 575193 + 627 29 IX87_RS04080 NZ_CP009257.1 794600 795550 − 951 29 IX87_RS04580 NZ_CP009257.1 893079 893567 + 489 29 IX87_RS06025 NZ_CP009257.1 1151701 1152729 − 1029 29 IX87_RS07135 NZ_CP009257.1 1390331 1391839 − 1509 29 IX87_RS09320 NZ_CP009257.1 1817676 1818305 + 630 29 IX87_RS09935 NZ_CP009257.1 1975228 1975761 + 534 29 IX87_RS10925 NZ_CP009257.1 2164138 2164779 + 642 29 IX87_RS12015 NZ_CP009257.1 2370258 2371046 + 789 29 IX87_RS13375 NZ_CP009257.1 2648241 2648681 + 441 29 IX87_RS14135 NZ_CP009257.1 2812384 2813133 − 750 29 IX87_RS20635 NZ_CP009257.1 4147315 4148835 + 1521 29 IX87_RS00375 NZ_CP009257.1 51997 54015 + 2019 28 IX87_RS02330 NZ_CP009257.1 429103 430266 + 1164 28 IX87_RS02720 NZ_CP009257.1 500533 501624 + 1092 28 IX87_RS05335 NZ_CP009257.1 1029021 1030466 + 1446 28 IX87_RS06300 NZ_CP009257.1 1210221 1211933 − 1713 28 IX87_RS06695 NZ_CP009257.1 1300065 1301135 + 1071 28 IX87_RS07140 NZ_CP009257.1 1392018 1392899 + 882 28 IX87_RS07210 NZ_CP009257.1 1406215 1406670 − 456 28 IX87_RS07230 NZ_CP009257.1 1409031 1410200 − 1170 28 IX87_RS09980 NZ_CP009257.1 1984041 1984688 − 648 28 IX87_RS10705 NZ_CP009257.1 2117557 2118675 + 1119 28 IX87_RS10960 NZ_CP009257.1 2172393 2173463 − 1071 28 IX87_RS11040 NZ_CP009257.1 2189378 2190064 − 687 28 IX87_RS11045 NZ_CP009257.1 2190084 2191742 − 1659 28 IX87_RS11555 NZ_CP009257.1 2290486 2291013 + 528 28 IX87_RS11980 NZ_CP009257.1 2361763 2362581 − 819 28 IX87_RS12005 NZ_CP009257.1 2368404 2369006 + 603 28 IX87_RS12320 NZ_CP009257.1 2430928 2431476 − 549 28 IX87_RS12610 NZ_CP009257.1 2492421 2493305 + 885 28 IX87_RS13380 NZ_CP009257.1 2648779 2649681 − 903 28 IX87_RS13495 NZ_CP009257.1 2673584 2674129 − 546 28 IX87_RS14130 NZ_CP009257.1 2811287 2812369 − 1083 28 IX87_RS15105 NZ_CP009257.1 3014688 3015116 + 429 28 IX87_RS15195 NZ_CP009257.1 3034100 3034600 + 501 28 IX87_RS15440 NZ_CP009257.1 3082866 3083681 − 816 28 IX87_RS16045 NZ_CP009257.1 3212772 3213983 + 1212 28 IX87_RS16160 NZ_CP009257.1 3236100 3236510 + 411 28 IX87_RS16410 NZ_CP009257.1 3288317 3290227 − 1911 28 IX87_RS16650 NZ_CP009257.1 3332025 3334313 − 2289 28 IX87_RS17050 NZ_CP009257.1 3424098 3424916 + 819 28 IX87_RS18105 NZ_CP009257.1 3642853 3643527 + 675 28 IX87_RS20645 NZ_CP009257.1 4149512 4150183 − 672 28 IX87_RS00365 NZ_CP009257.1 49867 51117 − 1251 27 IX87_RS01630 NZ_CP009257.1 304069 304524 − 456 27 IX87_RS03765 NZ_CP009257.1 722980 724137 − 1158 27 IX87_RS03815 NZ_CP009257.1 732520 735201 − 2682 27 IX87_RS05490 NZ_CP009257.1 1062592 1063254 + 663 27 IX87_RS05615 NZ_CP009257.1 1090725 1091357 − 633 27 IX87_RS06385 NZ_CP009257.1 1229277 1231226 − 1950 27 IX87_RS06560 NZ_CP009257.1 1271031 1272167 − 1137 27 IX87_RS08805 NZ_CP009257.1 1714120 1715514 − 1395 27 IX87_RS11395 NZ_CP009257.1 2259754 2260563 − 810 27 IX87_RS12495 NZ_CP009257.1 2468319 2468978 − 660 27 IX87_RS13465 NZ_CP009257.1 2667713 2668063 + 351 27 IX87_RS13605 NZ_CP009257.1 2696850 2697389 + 540 27 IX87_RS15540 NZ_CP009257.1 3103545 3104279 + 735 27 IX87_RS16400 NZ_CP009257.1 3286484 3287419 − 936 27 IX87_RS16530 NZ_CP009257.1 3309296 3310186 + 891 27 IX87_RS16565 NZ_CP009257.1 3314709 3315551 − 843 27 IX87_RS18945 NZ_CP009257.1 3799276 3800400 + 1125 27 IX87_RS20795 NZ_CP009257.1 4177117 4177911 − 795 27 IX87_RS01645 NZ_CP009257.1 306637 307545 − 909 26 IX87_RS02255 NZ_CP009257.1 414290 416017 − 1728 26 IX87_RS02800 NZ_CP009257.1 515587 516894 + 1308 26 IX87_RS04225 NZ_CP009257.1 825027 825773 − 747 26 IX87_RS05300 NZ_CP009257.1 1021581 1022816 − 1236 26 IX87_RS05540 NZ_CP009257.1 1077605 1079248 + 1644 26 IX87_RS07020 NZ_CP009257.1 1363028 1363261 + 234 26 IX87_RS07225 NZ_CP009257.1 1408613 1408993 + 381 26 IX87_RS07260 NZ_CP009257.1 1412820 1413605 + 786 26 IX87_RS08325 NZ_CP009257.1 1601239 1602045 + 807 26 IX87_RS08850 NZ_CP009257.1 1726097 1727416 + 1320 26 IX87_RS09745 NZ_CP009257.1 1919039 1919575 + 537 26 IX87_RS09985 NZ_CP009257.1 1984977 1985234 − 258 26 IX87_RS12245 NZ_CP009257.1 2417012 2417380 − 369 26 IX87_RS12365 NZ_CP009257.1 2439691 2440641 − 951 26 IX87_RS13950 NZ_CP009257.1 2766605 2767258 − 654 26 IX87_RS14610 NZ_CP009257.1 2906314 2907189 + 876 26 IX87_RS14630 NZ_CP009257.1 2911289 2912659 − 1371 26 IX87_RS14925 NZ_CP009257.1 2981040 2982257 − 1218 26 IX87_RS15890 NZ_CP009257.1 3173363 3174166 + 804 26 IX87_RS16055 NZ_CP009257.1 3214571 3215527 − 957 26 IX87_RS16195 NZ_CP009257.1 3242618 3243913 − 1296 26 IX87_RS16850 NZ_CP009257.1 3378625 3380619 − 1995 26 IX87_RS17240 NZ_CP009257.1 3464514 3465431 − 918 26 IX87_RS18210 NZ_CP009257.1 3660381 3660854 − 474 26 IX87_RS18685 NZ_CP009257.1 3746588 3747961 − 1374 26 IX87_RS18940 NZ_CP009257.1 3798374 3798970 + 597 26 IX87_RS20760 NZ_CP009257.1 4172105 4172338 + 234 26 IX87_RS21220 NZ_CP009257.1 4249442 4250230 − 789 26 IX87_RS21355 NZ_CP009257.1 4275991 4276359 + 369 26 IX87_RS01800 NZ_CP009257.1 339703 340731 + 1029 25 IX87_RS02275 NZ_CP009257.1 418027 418809 − 783 25 IX87_RS02555 NZ_CP009257.1 473120 474037 + 918 25 IX87_RS05550 NZ_CP009257.1 1080014 1080877 − 864 25 IX87_RS08630 NZ_CP009257.1 1672235 1673368 + 1134 25 IX87_RS08880 NZ_CP009257.1 1732783 1734033 + 1251 25 IX87_RS09215 NZ_CP009257.1 1797566 1798570 + 1005 25 IX87_RS09345 NZ_CP009257.1 1823803 1824489 − 687 25 IX87_RS09655 NZ_CP009257.1 1901094 1902032 − 939 25 IX87_RS10005 NZ_CP009257.1 1986851 1987828 + 978 25 IX87_RS11370 NZ_CP009257.1 2254737 2255240 + 504 25 IX87_RS12500 NZ_CP009257.1 2468994 2470076 − 1083 25 IX87_RS13615 NZ_CP009257.1 2698026 2699336 + 1311 25 IX87_RS13975 NZ_CP009257.1 2770515 2773640 − 3126 25 IX87_RS16005 NZ_CP009257.1 3196529 3197947 + 1419 25 IX87_RS16275 NZ_CP009257.1 3259569 3260621 + 1053 25 IX87_RS16635 NZ_CP009257.1 3327836 3328996 − 1161 25 IX87_RS18120 NZ_CP009257.1 3646451 3647011 + 561 25 IX87_RS18900 NZ_CP009257.1 3792449 3792649 + 201 25 IX87_RS20660 NZ_CP009257.1 4152646 4153983 + 1338 25 IX87_RS02320 NZ_CP009257.1 428096 428479 + 384 24 IX87_RS03665 NZ_CP009257.1 700843 701157 − 315 24 IX87_RS04315 NZ_CP009257.1 839662 839877 − 216 24 IX87_RS04590 NZ_CP009257.1 896505 897311 + 807 24 IX87_RS06080 NZ_CP009257.1 1165968 1167227 − 1260 24 IX87_RS06770 NZ_CP009257.1 1316709 1317404 + 696 24 IX87_RS07165 NZ_CP009257.1 1396045 1397472 − 1428 24 IX87_RS07310 NZ_CP009257.1 1423947 1425092 − 1146 24 IX87_RS07795 NZ_CP009257.1 1509034 1509861 + 828 24 IX87_RS08835 NZ_CP009257.1 1720677 1721465 + 789 24 IX87_RS09370 NZ_CP009257.1 1828805 1829884 − 1080 24 IX87_RS09595 NZ_CP009257.1 1877699 1878604 − 906 24 IX87_RS09775 NZ_CP009257.1 1926318 1926755 + 438 24 IX87_RS09790 NZ_CP009257.1 1927934 1929658 − 1725 24 IX87_RS10050 NZ_CP009257.1 1998020 1998826 − 807 24 IX87_RS11080 NZ_CP009257.1 2198122 2199585 − 1464 24 IX87_RS11425 NZ_CP009257.1 2264611 2265423 − 813 24 IX87_RS11915 NZ_CP009257.1 2348762 2349634 − 873 24 IX87_RS12965 NZ_CP009257.1 2556772 2557653 − 882 24 IX87_RS13120 NZ_CP009257.1 2589460 2590902 − 1443 24 IX87_RS13815 NZ_CP009257.1 2742868 2743647 + 780 24 IX87_RS14025 NZ_CP009257.1 2786496 2787800 + 1305 24 IX87_RS14915 NZ_CP009257.1 2979708 2980349 − 642 24 IX87_RS15390 NZ_CP009257.1 3072722 3073906 + 1185 24 IX87_RS15975 NZ_CP009257.1 3189841 3190614 − 774 24 IX87_RS16015 NZ_CP009257.1 3198648 3202283 + 3636 24 IX87_RS17315 NZ_CP009257.1 3478991 3480466 + 1476 24 IX87_RS17335 NZ_CP009257.1 3482626 3483309 + 684 24 IX87_RS17425 NZ_CP009257.1 3502154 3502840 + 687 24 IX87_RS17805 NZ_CP009257.1 3581518 3582153 + 636 24 IX87_RS17855 NZ_CP009257.1 3589778 3590923 − 1146 24 IX87_RS17930 NZ_CP009257.1 3606721 3609171 + 2451 24 IX87_RS18165 NZ_CP009257.1 3650001 3650834 − 834 24 IX87_RS18185 NZ_CP009257.1 3654514 3656379 − 1866 24 IX87_RS18510 NZ_CP009257.1 3708769 3710559 + 1791 24 IX87_RS18980 NZ_CP009257.1 3803807 3804193 + 387 24 IX87_RS19000 NZ_CP009257.1 3807756 3808760 + 1005 24 IX87_RS20605 NZ_CP009257.1 4140685 4141740 − 1056 24 IX87_RS20665 NZ_CP009257.1 4154025 4155176 − 1152 24 IX87_RS03670 NZ_CP009257.1 701166 702104 − 939 23 IX87_RS05310 NZ_CP009257.1 1023693 1025123 + 1431 23 IX87_RS05545 NZ_CP009257.1 1079248 1079991 + 744 23 IX87_RS05625 NZ_CP009257.1 1091979 1092263 + 285 23 IX87_RS07220 NZ_CP009257.1 1407834 1408409 − 576 23 IX87_RS08625 NZ_CP009257.1 1671742 1672230 + 489 23 IX87_RS08855 NZ_CP009257.1 1727515 1728801 + 1287 23 IX87_RS09060 NZ_CP009257.1 1766393 1767220 − 828 23 IX87_RS09910 NZ_CP009257.1 1970874 1971398 − 525 23 IX87_RS09930 NZ_CP009257.1 1974494 1975147 + 654 23 IX87_RS11430 NZ_CP009257.1 2265447 2266430 − 984 23 IX87_RS13110 NZ_CP009257.1 2586453 2587745 − 1293 23 IX87_RS13265 NZ_CP009257.1 2623493 2624068 + 576 23 IX87_RS14370 NZ_CP009257.1 2856005 2856535 − 531 23 IX87_RS15495 NZ_CP009257.1 3093257 3095134 − 1878 23 IX87_RS16755 NZ_CP009257.1 3361857 3362057 + 201 23 IX87_RS16780 NZ_CP009257.1 3365577 3366692 + 1116 23 IX87_RS18525 NZ_CP009257.1 3714445 3715383 + 939 23 IX87_RS18550 NZ_CP009257.1 3719775 3720632 + 858 23 IX87_RS20745 NZ_CP009257.1 4169889 4170995 − 1107 23 IX87_RS20810 NZ_CP009257.1 4180436 4180681 + 246 23 IX87_RS00625 NZ_CP009257.1 103429 104763 − 1335 22 IX87_RS02130 NZ_CP009257.1 394677 395654 − 978 22 IX87_RS03500 NZ_CP009257.1 667769 668491 − 723 22 IX87_RS03760 NZ_CP009257.1 722445 722900 + 456 22 IX87_RS03865 NZ_CP009257.1 746631 748112 − 1482 22 IX87_RS04180 NZ_CP009257.1 815567 815890 + 324 22 IX87_RS04260 NZ_CP009257.1 830546 831175 − 630 22 IX87_RS04555 NZ_CP009257.1 887192 888436 − 1245 22 IX87_RS05605 NZ_CP009257.1 1088095 1089303 − 1209 22 IX87_RS06000 NZ_CP009257.1 1146413 1146985 + 573 22 IX87_RS06745 NZ_CP009257.1 1311150 1311419 + 270 22 IX87_RS06805 NZ_CP009257.1 1323261 1324628 − 1368 22 IX87_RS09130 NZ_CP009257.1 1781059 1781982 + 924 22 IX87_RS09145 NZ_CP009257.1 1784017 1784727 + 711 22 IX87_RS09650 NZ_CP009257.1 1900355 1901113 − 759 22 IX87_RS10590 NZ_CP009257.1 2095487 2096701 − 1215 22 IX87_RS11245 NZ_CP009257.1 2230960 2231289 + 330 22 IX87_RS11290 NZ_CP009257.1 2239186 2239665 + 480 22 IX87_RS12400 NZ_CP009257.1 2445716 2447344 − 1629 22 IX87_RS13645 NZ_CP009257.1 2704726 2706084 + 1359 22 IX87_RS13660 NZ_CP009257.1 2708418 2709266 − 849 22 IX87_RS13870 NZ_CP009257.1 2753075 2754340 − 1266 22 IX87_RS14115 NZ_CP009257.1 2807693 2808250 + 558 22 IX87_RS14325 NZ_CP009257.1 2848112 2848597 + 486 22 IX87_RS14365 NZ_CP009257.1 2855521 2856003 − 483 22 IX87_RS15330 NZ_CP009257.1 3060680 3062077 + 1398 22 IX87_RS15555 NZ_CP009257.1 3106078 3106917 + 840 22 IX87_RS15955 NZ_CP009257.1 3183394 3183762 − 369 22 IX87_RS16430 NZ_CP009257.1 3292188 3292637 + 450 22 IX87_RS16540 NZ_CP009257.1 3311378 3311998 + 621 22 IX87_RS18175 NZ_CP009257.1 3651436 3653073 − 1638 22 IX87_RS18640 NZ_CP009257.1 3736733 3737380 − 648 22 IX87_RS20290 NZ_CP009257.1 4076022 4076738 + 717 22 IX87_RS20630 NZ_CP009257.1 4146077 4147132 − 1056 22 IX87_RS20790 NZ_CP009257.1 4176163 4177065 + 903 22 IX87_RS00840 NZ_CP009257.1 149665 151731 − 2067 21 IX87_RS04175 NZ_CP009257.1 814691 815221 + 531 21 IX87_RS06620 NZ_CP009257.1 1281827 1283074 − 1248 21 IX87_RS06815 NZ_CP009257.1 1325905 1326633 − 729 21 IX87_RS09275 NZ_CP009257.1 1808267 1808587 + 321 21 IX87_RS10495 NZ_CP009257.1 2076160 2077017 − 858 21 IX87_RS10555 NZ_CP009257.1 2086872 2087870 − 999 21 IX87_RS10775 NZ_CP009257.1 2133402 2134226 + 825 21 IX87_RS11240 NZ_CP009257.1 2229728 2230861 + 1134 21 IX87_RS11945 NZ_CP009257.1 2357105 2357506 − 402 21 IX87_RS12210 NZ_CP009257.1 2409670 2410788 + 1119 21 IX87_RS13860 NZ_CP009257.1 2751732 2751935 + 204 21 IX87_RS15935 NZ_CP009257.1 3180364 3180768 − 405 21 IX87_RS16670 NZ_CP009257.1 3338423 3339139 + 717 21 IX87_RS16700 NZ_CP009257.1 3347639 3348259 + 621 21 IX87_RS16790 NZ_CP009257.1 3368010 3368708 + 699 21 IX87_RS00850 NZ_CP009257.1 153725 154360 + 636 20 IX87_RS02465 NZ_CP009257.1 456673 457233 − 561 20 IX87_RS03235 NZ_CP009257.1 605657 607066 − 1410 20 IX87_RS03680 NZ_CP009257.1 704516 705895 − 1380 20 IX87_RS04075 NZ_CP009257.1 793538 793996 − 459 20 IX87_RS05010 NZ_CP009257.1 958689 959078 − 390 20 IX87_RS06040 NZ_CP009257.1 1154918 1155421 − 504 20 IX87_RS06715 NZ_CP009257.1 1303340 1304890 − 1551 20 IX87_RS07240 NZ_CP009257.1 1410873 1411118 + 246 20 IX87_RS07340 NZ_CP009257.1 1432109 1432660 + 552 20 IX87_RS09305 NZ_CP009257.1 1814561 1815259 − 699 20 IX87_RS09615 NZ_CP009257.1 1881832 1884927 − 3096 20 IX87_RS09740 NZ_CP009257.1 1918701 1919024 + 324 20 IX87_RS09765 NZ_CP009257.1 1925008 1925484 + 477 20 IX87_RS10125 NZ_CP009257.1 2016851 2017657 + 807 20 IX87_RS10435 NZ_CP009257.1 2064195 2064995 + 801 20 IX87_RS10580 NZ_CP009257.1 2094041 2094244 − 204 20 IX87_RS10665 NZ_CP009257.1 2106785 2107921 + 1137 20 IX87_RS10810 NZ_CP009257.1 2140199 2141659 + 1461 20 IX87_RS10835 NZ_CP009257.1 2145504 2146679 + 1176 20 IX87_RS10880 NZ_CP009257.1 2156493 2157698 + 1206 20 IX87_RS11155 NZ_CP009257.1 2213291 2214046 − 756 20 IX87_RS11340 NZ_CP009257.1 2247266 2248639 + 1374 20 IX87_RS11905 NZ_CP009257.1 2346396 2347346 + 951 20 IX87_RS12370 NZ_CP009257.1 2440764 2441393 + 630 20 IX87_RS12605 NZ_CP009257.1 2490884 2492302 + 1419 20 IX87_RS12805 NZ_CP009257.1 2529934 2530692 + 759 20 IX87_RS13150 NZ_CP009257.1 2595025 2596107 − 1083 20 IX87_RS14080 NZ_CP009257.1 2799025 2800152 + 1128 20 IX87_RS14320 NZ_CP009257.1 2846826 2847896 + 1071 20 IX87_RS14780 NZ_CP009257.1 2948111 2949628 + 1518 20 IX87_RS15190 NZ_CP009257.1 3031408 3033786 + 2379 20 IX87_RS15725 NZ_CP009257.1 3140768 3141472 − 705 20 IX87_RS16240 NZ_CP009257.1 3254106 3255038 + 933 20 IX87_RS16855 NZ_CP009257.1 3380622 3381959 − 1338 20 IX87_RS18170 NZ_CP009257.1 3650853 3651431 − 579 20 IX87_RS18180 NZ_CP009257.1 3653234 3654517 + 1284 20 IX87_RS18650 NZ_CP009257.1 3738539 3738889 + 351 20 IX87_RS21120 NZ_CP009257.1 4231326 4231769 + 444 20 IX87_RS01655 NZ_CP009257.1 309178 309630 − 453 19 IX87_RS01690 NZ_CP009257.1 316505 316777 + 273 19 IX87_RS02325 NZ_CP009257.1 428479 429072 + 594 19 IX87_RS02440 NZ_CP009257.1 451654 452061 + 408 19 IX87_RS03300 NZ_CP009257.1 616001 616672 − 672 19 IX87_RS03310 NZ_CP009257.1 618536 619129 − 594 19 IX87_RS06255 NZ_CP009257.1 1201373 1201930 − 558 19 IX87_RS06290 NZ_CP009257.1 1208869 1209696 + 828 19 IX87_RS06565 NZ_CP009257.1 1272186 1272956 − 771 19 IX87_RS07855 NZ_CP009257.1 1523492 1524214 + 723 19 IX87_RS08575 NZ_CP009257.1 1660477 1660878 − 402 19 IX87_RS08665 NZ_CP009257.1 1679905 1680762 − 858 19 IX87_RS08775 NZ_CP009257.1 1707046 1707429 − 384 19 IX87_RS08925 NZ_CP009257.1 1743568 1744224 + 657 19 IX87_RS09385 NZ_CP009257.1 1832949 1834019 + 1071 19 IX87_RS09450 NZ_CP009257.1 1848330 1848554 − 225 19 IX87_RS11375 NZ_CP009257.1 2255369 2256469 + 1101 19 IX87_RS12185 NZ_CP009257.1 2406181 2406975 + 795 19 IX87_RS12745 NZ_CP009257.1 2521886 2522269 − 384 19 IX87_RS12750 NZ_CP009257.1 2522372 2522965 + 594 19 IX87_RS13210 NZ_CP009257.1 2609332 2610012 − 681 19 IX87_RS13555 NZ_CP009257.1 2684754 2686097 + 1344 19 IX87_RS13625 NZ_CP009257.1 2700607 2701992 + 1386 19 IX87_RS15110 NZ_CP009257.1 3015189 3017303 + 2115 19 IX87_RS16260 NZ_CP009257.1 3257191 3257868 − 678 19 IX87_RS16465 NZ_CP009257.1 3299692 3300225 + 534 19 IX87_RS16535 NZ_CP009257.1 3310617 3311333 + 717 19 IX87_RS17995 NZ_CP009257.1 3622567 3624603 + 2037 19 IX87_RS18195 NZ_CP009257.1 3657767 3658819 + 1053 19 IX87_RS18580 NZ_CP009257.1 3724097 3725029 + 933 19 IX87_RS20655 NZ_CP009257.1 4151977 4152627 + 651 19 IX87_RS21260 NZ_CP009257.1 4258280 4259032 − 753 19 IX87_RS00345 NZ_CP009257.1 45729 47132 − 1404 18 IX87_RS00580 NZ_CP009257.1 92247 93272 + 1026 18 IX87_RS00830 NZ_CP009257.1 148262 148777 − 516 18 IX87_RS02355 NZ_CP009257.1 434269 434805 + 537 18 IX87_RS03625 NZ_CP009257.1 692808 694097 − 1290 18 IX87_RS05535 NZ_CP009257.1 1076093 1077472 + 1380 18 IX87_RS06085 NZ_CP009257.1 1167300 1168154 − 855 18 IX87_RS06225 NZ_CP009257.1 1195205 1197475 + 2271 18 IX87_RS06400 NZ_CP009257.1 1232832 1233140 + 309 18 IX87_RS06475 NZ_CP009257.1 1252040 1253362 + 1323 18 IX87_RS06545 NZ_CP009257.1 1267596 1268372 − 777 18 IX87_RS06880 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IX87_RS13655 NZ_CP009257.1 2707570 2708421 − 852 12 IX87_RS13735 NZ_CP009257.1 2723214 2723852 − 639 12 IX87_RS13780 NZ_CP009257.1 2734929 2736041 + 1113 12 IX87_RS14020 NZ_CP009257.1 2785537 2786499 + 963 12 IX87_RS14465 NZ_CP009257.1 2875030 2875668 − 639 12 IX87_RS14665 NZ_CP009257.1 2921094 2921978 + 885 12 IX87_RS14895 NZ_CP009257.1 2977186 2977578 + 393 12 IX87_RS14955 NZ_CP009257.1 2987282 2987689 + 408 12 IX87_RS15280 NZ_CP009257.1 3051012 3052328 − 1317 12 IX87_RS15835 NZ_CP009257.1 3162242 3162682 − 441 12 IX87_RS15855 NZ_CP009257.1 3166531 3166857 + 327 12 IX87_RS15885 NZ_CP009257.1 3171369 3173081 − 1713 12 IX87_RS15940 NZ_CP009257.1 3180781 3181056 − 276 12 IX87_RS16845 NZ_CP009257.1 3377208 3378602 − 1395 12 IX87_RS17030 NZ_CP009257.1 3418419 3419285 − 867 12 IX87_RS17735 NZ_CP009257.1 3565317 3565943 − 627 12 IX87_RS17960 NZ_CP009257.1 3614557 3615309 − 753 12 IX87_RS18050 NZ_CP009257.1 3635188 3635784 − 597 12 IX87_RS18585 NZ_CP009257.1 3725109 3725465 + 357 12 IX87_RS18605 NZ_CP009257.1 3731267 3731605 − 339 12 IX87_RS18665 NZ_CP009257.1 3741368 3742333 − 966 12 IX87_RS18755 NZ_CP009257.1 3764136 3764756 + 621 12 IX87_RS19030 NZ_CP009257.1 3814958 3815920 + 963 12 IX87_RS19110 NZ_CP009257.1 3831820 3833169 − 1350 12 IX87_RS19180 NZ_CP009257.1 3847835 3848731 + 897 12 IX87_RS20580 NZ_CP009257.1 4135765 4136481 − 717 12 IX87_RS20625 NZ_CP009257.1 4145243 4146001 − 759 12 IX87_RS20775 NZ_CP009257.1 4173772 4174980 − 1209 12 IX87_RS21140 NZ_CP009257.1 4235999 4237177 − 1179 12 IX87_RS21180 NZ_CP009257.1 4243959 4244252 − 294 12 IX87_RS00895 NZ_CP009257.1 163669 165546 − 1878 11 IX87_RS01610 NZ_CP009257.1 301524 301961 − 438 11 IX87_RS02565 NZ_CP009257.1 474867 476282 + 1416 11 IX87_RS03280 NZ_CP009257.1 611881 612171 + 291 11 IX87_RS03635 NZ_CP009257.1 695359 696897 − 1539 11 IX87_RS04500 NZ_CP009257.1 876236 876451 + 216 11 IX87_RS06285 NZ_CP009257.1 1207744 1208835 + 1092 11 IX87_RS09070 NZ_CP009257.1 1769283 1769735 − 453 11 IX87_RS09390 NZ_CP009257.1 1834016 1835107 + 1092 11 IX87_RS09665 NZ_CP009257.1 1904298 1905815 − 1518 11 IX87_RS10690 NZ_CP009257.1 2115807 2116169 − 363 11 IX87_RS10895 NZ_CP009257.1 2160289 2161149 + 861 11 IX87_RS11495 NZ_CP009257.1 2278653 2279816 − 1164 11 IX87_RS11695 NZ_CP009257.1 2317270 2317701 + 432 11 IX87_RS11940 NZ_CP009257.1 2356467 2357102 + 636 11 IX87_RS12325 NZ_CP009257.1 2431496 2431747 − 252 11 IX87_RS12915 NZ_CP009257.1 2550523 2550933 − 411 11 IX87_RS13305 NZ_CP009257.1 2631194 2632894 − 1701 11 IX87_RS13455 NZ_CP009257.1 2665744 2666394 − 651 11 IX87_RS13945 NZ_CP009257.1 2765375 2766565 + 1191 11 IX87_RS14990 NZ_CP009257.1 2995020 2995829 − 810 11 IX87_RS15210 NZ_CP009257.1 3036478 3037236 − 759 11 IX87_RS15415 NZ_CP009257.1 3076544 3078067 − 1524 11 IX87_RS16985 NZ_CP009257.1 3410236 3411420 − 1185 11 IX87_RS17270 NZ_CP009257.1 3469412 3470236 − 825 11 IX87_RS17390 NZ_CP009257.1 3496513 3497139 + 627 11 IX87_RS18100 NZ_CP009257.1 3641988 3642755 − 768 11 IX87_RS18130 NZ_CP009257.1 3647579 3648160 − 582 11 IX87_RS18615 NZ_CP009257.1 3733522 3734040 − 519 11 IX87_RS18775 NZ_CP009257.1 3768473 3769528 + 1056 11 IX87_RS19255 NZ_CP009257.1 3861585 3862370 + 786 11 IX87_RS20575 NZ_CP009257.1 4134651 4135745 − 1095 11 IX87_RS21380 NZ_CP009257.1 4278378 4279781 + 1404 11 IX87_RS00395 NZ_CP009257.1 55826 56491 − 666 10 IX87_RS00820 NZ_CP009257.1 146453 147451 − 999 10 IX87_RS01570 NZ_CP009257.1 291456 291908 − 453 10 IX87_RS02185 NZ_CP009257.1 403908 404411 − 504 10 IX87_RS02240 NZ_CP009257.1 411514 412494 − 981 10 IX87_RS02385 NZ_CP009257.1 439526 439900 + 375 10 IX87_RS02430 NZ_CP009257.1 450213 450803 + 591 10 IX87_RS02610 NZ_CP009257.1 480900 481763 − 864 10 IX87_RS02815 NZ_CP009257.1 522464 523279 + 816 10 IX87_RS02920 NZ_CP009257.1 543306 544101 − 796 10 IX87_RS03135 NZ_CP009257.1 582536 584497 + 1962 10 IX87_RS03640 NZ_CP009257.1 696900 697691 − 792 10 IX87_RS03650 NZ_CP009257.1 698473 699534 − 1062 10 IX87_RS03805 NZ_CP009257.1 730021 731385 − 1365 10 IX87_RS04065 NZ_CP009257.1 791722 792969 + 1248 10 IX87_RS04300 NZ_CP009257.1 836916 837374 − 459 10 IX87_RS05220 NZ_CP009257.1 1006056 1006769 + 714 10 IX87_RS05325 NZ_CP009257.1 1026767 1027474 + 708 10 IX87_RS05580 NZ_CP009257.1 1084582 1085184 + 603 10 IX87_RS06705 NZ_CP009257.1 1301939 1302718 − 780 10 IX87_RS06830 NZ_CP009257.1 1329202 1330008 − 807 10 IX87_RS07275 NZ_CP009257.1 1415264 1415917 + 654 10 IX87_RS08645 NZ_CP009257.1 1675642 1676283 + 642 10 IX87_RS08740 NZ_CP009257.1 1698523 1699218 + 696 10 IX87_RS09810 NZ_CP009257.1 1930889 1932196 − 1308 10 IX87_RS09950 NZ_CP009257.1 1978637 1979197 − 561 10 IX87_RS10675 NZ_CP009257.1 2108418 2112938 − 4521 10 IX87_RS10920 NZ_CP009257.1 2163505 2164011 − 507 10 IX87_RS11075 NZ_CP009257.1 2197481 2197927 + 447 10 IX87_RS11260 NZ_CP009257.1 2234280 2235533 − 1254 10 IX87_RS11420 NZ_CP009257.1 2263771 2264610 − 840 10 IX87_RS11450 NZ_CP009257.1 2268261 2268689 + 429 10 IX87_RS11625 NZ_CP009257.1 2304280 2305194 − 915 10 IX87_RS12060 NZ_CP009257.1 2379693 2380955 − 1263 10 IX87_RS12240 NZ_CP009257.1 2416652 2416966 + 315 10 IX87_RS12575 NZ_CP009257.1 2486050 2486973 − 924 10 IX87_RS13075 NZ_CP009257.1 2579131 2579514 − 384 10 IX87_RS13080 NZ_CP009257.1 2579562 2580389 − 828 10 IX87_RS13155 NZ_CP009257.1 2596370 2597044 + 675 10 IX87_RS13505 NZ_CP009257.1 2674837 2675856 + 1020 10 IX87_RS13730 NZ_CP009257.1 2722390 2723190 − 801 10 IX87_RS13805 NZ_CP009257.1 2741370 2742002 + 633 10 IX87_RS13810 NZ_CP009257.1 2742020 2742568 + 549 10 IX87_RS14155 NZ_CP009257.1 2816265 2816585 + 321 10 IX87_RS14220 NZ_CP009257.1 2827087 2828247 − 1161 10 IX87_RS14315 NZ_CP009257.1 2846289 2846615 − 327 10 IX87_RS14785 NZ_CP009257.1 2949640 2950530 + 891 10 IX87_RS15085 NZ_CP009257.1 3011073 3011642 − 570 10 IX87_RS15445 NZ_CP009257.1 3083828 3084748 − 921 10 IX87_RS15790 NZ_CP009257.1 3152376 3154175 + 1800 10 IX87_RS15815 NZ_CP009257.1 3157576 3158349 − 774 10 IX87_RS15945 NZ_CP009257.1 3181053 3181580 − 528 10 IX87_RS16060 NZ_CP009257.1 3215678 3216289 − 612 10 IX87_RS16255 NZ_CP009257.1 3256528 3257133 + 606 10 IX87_RS16325 NZ_CP009257.1 3270952 3271599 + 648 10 IX87_RS16545 NZ_CP009257.1 3311998 3312402 + 405 10 IX87_RS17345 NZ_CP009257.1 3484774 3485859 + 1086 10 IX87_RS17435 NZ_CP009257.1 3504119 3504514 + 396 10 IX87_RS17615 NZ_CP009257.1 3537246 3538541 − 1296 10 IX87_RS18030 NZ_CP009257.1 3631610 3632767 + 1158 10 IX87_RS18125 NZ_CP009257.1 3647067 3647447 − 381 10 IX87_RS18200 NZ_CP009257.1 3658830 3659567 + 738 10 IX87_RS18555 NZ_CP009257.1 3720690 3721424 + 735 10 IX87_RS18745 NZ_CP009257.1 3762142 3763665 + 1524 10 IX87_RS18990 NZ_CP009257.1 3805090 3806277 + 1188 10 IX87_RS19210 NZ_CP009257.1 3854282 3855163 − 882 10 IX87_RS19960 NZ_CP009257.1 4010432 4011925 − 1494 10 IX87_RS20430 NZ_CP009257.1 4104684 4105805 − 1122 10 IX87_RS20475 NZ_CP009257.1 4114472 4115791 − 1320 10 IX87_RS20540 NZ_CP009257.1 4127164 4127514 − 351 10 IX87_RS20640 NZ_CP009257.1 4148832 4149512 − 681 10 IX87_RS21335 NZ_CP009257.1 4272336 4272797 + 462 10 IX87_RS21340 NZ_CP009257.1 4272979 4273275 + 297 10 IX87_RS00500 NZ_CP009257.1 77208 77696 + 489 9 IX87_RS00890 NZ_CP009257.1 162280 163614 + 1335 9 IX87_RS01590 NZ_CP009257.1 294654 298250 + 3597 9 IX87_RS02265 NZ_CP009257.1 416458 417093 − 636 9 IX87_RS03590 NZ_CP009257.1 685352 685945 − 594 9 IX87_RS03660 NZ_CP009257.1 700075 700830 − 756 9 IX87_RS05005 NZ_CP009257.1 958057 958623 − 567 9 IX87_RS05100 NZ_CP009257.1 978078 979748 + 1671 9 IX87_RS05500 NZ_CP009257.1 1063532 1065646 + 2115 9 IX87_RS06510 NZ_CP009257.1 1258118 1260772 − 2655 9 IX87_RS07035 NZ_CP009257.1 1366588 1367970 − 1383 9 IX87_RS07835 NZ_CP009257.1 1520003 1520386 + 384 9 IX87_RS08410 NZ_CP009257.1 1619982 1621577 − 1596 9 IX87_RS08800 NZ_CP009257.1 1713156 1713971 − 816 9 IX87_RS09210 NZ_CP009257.1 1796958 1797557 + 600 9 IX87_RS09770 NZ_CP009257.1 1925563 1926195 + 633 9 IX87_RS10040 NZ_CP009257.1 1997100 1997534 + 435 9 IX87_RS10140 NZ_CP009257.1 2019175 2019543 − 369 9 IX87_RS11020 NZ_CP009257.1 2185105 2185818 + 714 9 IX87_RS11535 NZ_CP009257.1 2286877 2287944 − 1068 9 IX87_RS12195 NZ_CP009257.1 2407574 2408137 − 564 9 IX87_RS12875 NZ_CP009257.1 2541074 2541376 + 303 9 IX87_RS13170 NZ_CP009257.1 2597907 2598884 − 978 9 IX87_RS13520 NZ_CP009257.1 2676804 2678171 + 1368 9 IX87_RS15205 NZ_CP009257.1 3035421 3036476 − 1056 9 IX87_RS15550 NZ_CP009257.1 3105302 3106069 + 768 9 IX87_RS16940 NZ_CP009257.1 3400003 3400845 + 843 9 IX87_RS17455 NZ_CP009257.1 3508405 3508725 + 321 9 IX87_RS17810 NZ_CP009257.1 3582270 3582563 + 294 9 IX87_RS17865 NZ_CP009257.1 3592604 3593173 − 570 9 IX87_RS18025 NZ_CP009257.1 3630328 3631608 + 1281 9 IX87_RS18495 NZ_CP009257.1 3703539 3704420 − 882 9 IX87_RS18570 NZ_CP009257.1 3722638 3723144 + 507 9 IX87_RS19845 NZ_CP009257.1 3988611 3989285 + 675 9 IX87_RS21135 NZ_CP009257.1 4234497 4235951 + 1455 9 IX87_RS00290 NZ_CP009257.1 29786 30103 − 318 8 IX87_RS00390 NZ_CP009257.1 55187 55801 − 615 8 IX87_RS00570 NZ_CP009257.1 90692 91315 + 624 8 IX87_RS00810 NZ_CP009257.1 144434 144964 − 531 8 IX87_RS01575 NZ_CP009257.1 292288 292665 + 378 8 IX87_RS01745 NZ_CP009257.1 326804 327685 − 882 8 IX87_RS01780 NZ_CP009257.1 335566 336018 + 453 8 IX87_RS01810 NZ_CP009257.1 341009 341923 − 915 8 IX87_RS01820 NZ_CP009257.1 343529 344644 − 1116 8 IX87_RS02205 NZ_CP009257.1 407130 408089 − 960 8 IX87_RS02280 NZ_CP009257.1 418831 419463 − 633 8 IX87_RS02495 NZ_CP009257.1 461960 463018 + 1059 8 IX87_RS02835 NZ_CP009257.1 527309 528895 − 1587 8 IX87_RS02910 NZ_CP009257.1 541550 542431 − 882 8 IX87_RS02925 NZ_CP009257.1 544111 545151 − 1041 8 IX87_RS02980 NZ_CP009257.1 556532 557950 + 1419 8 IX87_RS03340 NZ_CP009257.1 626062 627003 − 942 8 IX87_RS03850 NZ_CP009257.1 743694 745505 − 1812 8 IX87_RS04265 NZ_CP009257.1 831560 832153 − 594 8 IX87_RS05055 NZ_CP009257.1 967998 968621 − 624 8 IX87_RS05150 NZ_CP009257.1 990657 991115 − 459 8 IX87_RS06075 NZ_CP009257.1 1165342 1165920 + 579 8 IX87_RS06370 NZ_CP009257.1 1226736 1227593 − 858 8 IX87_RS06555 NZ_CP009257.1 1269167 1270810 − 1644 8 IX87_RS06700 NZ_CP009257.1 1301188 1301898 − 711 8 IX87_RS06710 NZ_CP009257.1 1302721 1303317 − 597 8 IX87_RS23040 NZ_CP009257.1 1305554 1306123 + 570 8 IX87_RS07810 NZ_CP009257.1 1513071 1514285 + 1215 8 IX87_RS08440 NZ_CP009257.1 1627450 1630317 + 2868 8 IX87_RS08650 NZ_CP009257.1 1676333 1678519 − 2187 8 IX87_RS08670 NZ_CP009257.1 1680821 1682191 − 1371 8 IX87_RS08790 NZ_CP009257.1 1709830 1710213 + 384 8 IX87_RS08890 NZ_CP009257.1 1735856 1736761 + 906 8 IX87_RS08940 NZ_CP009257.1 1746777 1747421 − 645 8 IX87_RS09105 NZ_CP009257.1 1776473 1777480 + 1008 8 IX87_RS09280 NZ_CP009257.1 1808577 1808966 + 390 8 IX87_RS09360 NZ_CP009257.1 1826884 1827369 − 486 8 IX87_RS09905 NZ_CP009257.1 1969819 1970751 + 933 8 IX87_RS10035 NZ_CP009257.1 1996742 1997092 + 351 8 IX87_RS10120 NZ_CP009257.1 2016046 2016672 + 627 8 IX87_RS10425 NZ_CP009257.1 2061969 2062862 − 894 8 IX87_RS10450 NZ_CP009257.1 2067335 2068033 + 699 8 IX87_RS10530 NZ_CP009257.1 2082951 2084018 − 1068 8 IX87_RS10540 NZ_CP009257.1 2084936 2085991 − 1056 8 IX87_RS10585 NZ_CP009257.1 2094755 2095459 + 705 8 IX87_RS10680 NZ_CP009257.1 2113085 2115163 − 2079 8 IX87_RS10765 NZ_CP009257.1 2130498 2132585 − 2088 8 IX87_RS10770 NZ_CP009257.1 2132760 2133326 − 567 8 IX87_RS11015 NZ_CP009257.1 2184454 2185032 + 579 8 IX87_RS11230 NZ_CP009257.1 2227868 2228896 + 1029 8 IX87_RS11315 NZ_CP009257.1 2243076 2243498 − 423 8 IX87_RS11445 NZ_CP009257.1 2267601 2268254 + 654 8 IX87_RS11485 NZ_CP009257.1 2276030 2277835 − 1806 8 IX87_RS11505 NZ_CP009257.1 2280536 2280886 − 351 8 IX87_RS11720 NZ_CP009257.1 2323127 2323372 − 246 8 IX87_RS13115 NZ_CP009257.1 2587857 2589401 + 1545 8 IX87_RS13235 NZ_CP009257.1 2617126 2617776 − 651 8 IX87_RS13595 NZ_CP009257.1 2694574 2695089 − 516 8 IX87_RS13795 NZ_CP009257.1 2738329 2739717 − 1389 8 IX87_RS13820 NZ_CP009257.1 2743713 2744768 − 1056 8 IX87_RS14085 NZ_CP009257.1 2800280 2801125 + 846 8 IX87_RS14110 NZ_CP009257.1 2805510 2807441 + 1932 8 IX87_RS14170 NZ_CP009257.1 2819844 2820107 − 264 8 IX87_RS14200 NZ_CP009257.1 2823617 2824144 − 528 8 IX87_RS14435 NZ_CP009257.1 2870520 2870876 − 357 8 IX87_RS14495 NZ_CP009257.1 2881958 2882803 − 846 8 IX87_RS15250 NZ_CP009257.1 3043654 3044973 + 1320 8 IX87_RS15325 NZ_CP009257.1 3060284 3060622 + 339 8 IX87_RS15340 NZ_CP009257.1 3062710 3063795 + 1086 8 IX87_RS15860 NZ_CP009257.1 3166959 3167708 + 750 8 IX87_RS15870 NZ_CP009257.1 3168655 3169251 − 597 8 IX87_RS16080 NZ_CP009257.1 3221763 3222968 + 1206 8 IX87_RS16295 NZ_CP009257.1 3266406 3267056 + 651 8 IX87_RS16310 NZ_CP009257.1 3268045 3268905 − 861 8 IX87_RS16360 NZ_CP009257.1 3275979 3276776 − 798 8 IX87_RS16575 NZ_CP009257.1 3316047 3316406 − 360 8 IX87_RS16620 NZ_CP009257.1 3325867 3326490 − 624 8 IX87_RS16675 NZ_CP009257.1 3339164 3339718 − 555 8 IX87_RS16950 NZ_CP009257.1 3401874 3402686 + 813 8 IX87_RS16980 NZ_CP009257.1 3409083 3410087 − 1005 8 IX87_RS17000 NZ_CP009257.1 3413080 3414261 + 1182 8 IX87_RS17075 NZ_CP009257.1 3430359 3430769 + 411 8 IX87_RS17135 NZ_CP009257.1 3441683 3442111 + 429 8 IX87_RS17185 NZ_CP009257.1 3450307 3450603 + 297 8 IX87_RS17450 NZ_CP009257.1 3507464 3508255 + 792 8 IX87_RS17495 NZ_CP009257.1 3512483 3513478 − 996 8 IX87_RS17550 NZ_CP009257.1 3526663 3527592 − 930 8 IX87_RS17825 NZ_CP009257.1 3584366 3584785 − 420 8 IX87_RS17830 NZ_CP009257.1 3585078 3585305 + 228 8 IX87_RS17965 NZ_CP009257.1 3615340 3616143 + 804 8 IX87_RS18565 NZ_CP009257.1 3721960 3722625 + 666 8 IX87_RS18670 NZ_CP009257.1 3742505 3743728 + 1224 8 IX87_RS18845 NZ_CP009257.1 3784215 3785339 + 1125 8 IX87_RS19010 NZ_CP009257.1 3809961 3811190 − 1230 8 IX87_RS19025 NZ_CP009257.1 3813607 3814593 − 987 8 IX87_RS19040 NZ_CP009257.1 3816955 3818481 + 1527 8 IX87_RS19055 NZ_CP009257.1 3820737 3821795 + 1059 8 IX87_RS19105 NZ_CP009257.1 3831128 3831736 + 609 8 IX87_RS19155 NZ_CP009257.1 3840662 3841948 − 1287 8 IX87_RS19795 NZ_CP009257.1 3979005 3979748 + 744 8 IX87_RS20315 NZ_CP009257.1 4080278 4081198 + 921 8 IX87_RS20675 NZ_CP009257.1 4158388 4160484 − 2097 8 IX87_RS20705 NZ_CP009257.1 4164259 4164453 + 195 8 IX87_RS21170 NZ_CP009257.1 4242876 4243325 + 450 8 IX87_RS21310 NZ_CP009257.1 4268015 4268641 + 627 8 IX87_RS21370 NZ_CP009257.1 4277076 4277387 + 312 8 IX87_RS21385 NZ_CP009257.1 4279778 4280260 − 483 8 IX87_RS21390 NZ_CP009257.1 4280469 4281704 − 1236 8 IX87_RS00350 NZ_CP009257.1 47404 48195 + 792 7 IX87_RS00470 NZ_CP009257.1 69523 70035 − 513 7 IX87_RS01545 NZ_CP009257.1 286256 287407 − 1152 7 IX87_RS01595 NZ_CP009257.1 298452 299144 − 693 7 IX87_RS02180 NZ_CP009257.1 403395 403838 − 444 7 IX87_RS02410 NZ_CP009257.1 447103 447576 + 474 7 IX87_RS02540 NZ_CP009257.1 470347 471366 + 1020 7 IX87_RS02705 NZ_CP009257.1 497884 498717 + 834 7 IX87_RS02820 NZ_CP009257.1 523272 524087 + 816 7 IX87_RS04505 NZ_CP009257.1 876516 877103 − 588 7 IX87_RS06030 NZ_CP009257.1 1152729 1153859 − 1131 7 IX87_RS06415 NZ_CP009257.1 1234479 1234697 − 219 7 IX87_RS07270 NZ_CP009257.1 1414385 1415158 − 774 7 IX87_RS08675 NZ_CP009257.1 1682215 1683594 − 1380 7 IX87_RS09160 NZ_CP009257.1 1785960 1786646 + 687 7 IX87_RS09460 NZ_CP009257.1 1850591 1851979 + 1389 7 IX87_RS10950 NZ_CP009257.1 2171022 2171798 + 777 7 IX87_RS10980 NZ_CP009257.1 2176678 2177727 − 1050 7 IX87_RS11160 NZ_CP009257.1 2214043 2215071 − 1029 7 IX87_RS11475 NZ_CP009257.1 2273474 2275087 − 1614 7 IX87_RS12190 NZ_CP009257.1 2406991 2407524 + 534 7 IX87_RS13480 NZ_CP009257.1 2669887 2670969 + 1083 7 IX87_RS14165 NZ_CP009257.1 2818442 2819797 + 1356 7 IX87_RS14230 NZ_CP009257.1 2828823 2829779 − 957 7 IX87_RS14725 NZ_CP009257.1 2936060 2936434 + 375 7 IX87_RS14945 NZ_CP009257.1 2985876 2986181 + 306 7 IX87_RS14985 NZ_CP009257.1 2994392 2995018 + 627 7 IX87_RS15005 NZ_CP009257.1 2997255 2998058 + 804 7 IX87_RS15270 NZ_CP009257.1 3049840 3050250 + 411 7 IX87_RS15580 NZ_CP009257.1 3110165 3111001 + 837 7 IX87_RS15685 NZ_CP009257.1 3131661 3132158 − 498 7 IX87_RS16000 NZ_CP009257.1 3195614 3196321 − 708 7 IX87_RS16120 NZ_CP009257.1 3229501 3230112 + 612 7 IX87_RS17035 NZ_CP009257.1 3419296 3420084 − 789 7 IX87_RS18895 NZ_CP009257.1 3791894 3792319 + 426 7 IX87_RS21305 NZ_CP009257.1 4267411 4267893 − 483 7 IX87_RS00295 NZ_CP009257.1 30397 30738 − 342 6 IX87_RS00300 NZ_CP009257.1 30998 31564 + 567 6 IX87_RS00330 NZ_CP009257.1 43025 43504 + 480 6 IX87_RS00405 NZ_CP009257.1 57030 58730 − 1701 6 IX87_RS00635 NZ_CP009257.1 107022 110708 + 3687 6 IX87_RS01715 NZ_CP009257.1 322329 323060 + 732 6 IX87_RS02155 NZ_CP009257.1 399209 399907 − 699 6 IX87_RS02230 NZ_CP009257.1 410370 411143 − 774 6 IX87_RS02380 NZ_CP009257.1 438462 439487 + 1026 6 IX87_RS02475 NZ_CP009257.1 458526 459071 − 546 6 IX87_RS02490 NZ_CP009257.1 460441 461901 − 1461 6 IX87_RS02640 NZ_CP009257.1 485159 485629 − 471 6 IX87_RS02730 NZ_CP009257.1 502283 502990 + 708 6 IX87_RS02880 NZ_CP009257.1 535481 536167 − 687 6 IX87_RS02940 NZ_CP009257.1 546489 547664 + 1176 6 IX87_RS03040 NZ_CP009257.1 567533 568207 + 675 6 IX87_RS03200 NZ_CP009257.1 598376 598987 + 612 6 IX87_RS03225 NZ_CP009257.1 602525 603403 + 879 6 IX87_RS03655 NZ_CP009257.1 699558 700058 − 501 6 IX87_RS03700 NZ_CP009257.1 711163 711915 − 753 6 IX87_RS03745 NZ_CP009257.1 720113 720565 − 453 6 IX87_RS03875 NZ_CP009257.1 748625 749317 − 693 6 IX87_RS03985 NZ_CP009257.1 769280 770500 − 1221 6 IX87_RS21960 NZ_CP009257.1 794248 794442 − 195 6 IX87_RS04200 NZ_CP009257.1 818665 819276 − 612 6 IX87_RS04290 NZ_CP009257.1 835076 836182 − 1107 6 IX87_RS04380 NZ_CP009257.1 847999 848355 + 357 6 IX87_RS04515 NZ_CP009257.1 877600 879186 + 1587 6 IX87_RS04635 NZ_CP009257.1 904825 905850 − 1026 6 IX87_RS05030 NZ_CP009257.1 962671 962868 − 198 6 IX87_RS05035 NZ_CP009257.1 963267 964817 − 1551 6 IX87_RS05165 NZ_CP009257.1 993543 994994 + 1452 6 IX87_RS05170 NZ_CP009257.1 995076 996962 + 1887 6 IX87_RS05195 NZ_CP009257.1 1000565 1001569 + 1005 6 IX87_RS05510 NZ_CP009257.1 1067135 1068724 − 1590 6 IX87_RS05565 NZ_CP009257.1 1082264 1083100 + 837 6 IX87_RS06215 NZ_CP009257.1 1192967 1193218 − 252 6 IX87_RS06280 NZ_CP009257.1 1207269 1207526 + 258 6 IX87_RS06295 NZ_CP009257.1 1209818 1210183 − 366 6 IX87_RS06340 NZ_CP009257.1 1221390 1222112 + 723 6 IX87_RS06420 NZ_CP009257.1 1234951 1235403 + 453 6 IX87_RS06485 NZ_CP009257.1 1254048 1254596 − 549 6 IX87_RS06575 NZ_CP009257.1 1274158 1274979 − 822 6 IX87_RS06795 NZ_CP009257.1 1321605 1322723 + 1119 6 IX87_RS06810 NZ_CP009257.1 1324979 1325890 + 912 6 IX87_RS07015 NZ_CP009257.1 1361755 1362729 − 975 6 IX87_RS07250 NZ_CP009257.1 1412230 1412595 + 366 6 IX87_RS07255 NZ_CP009257.1 1412609 1412806 + 198 6 IX87_RS07435 NZ_CP009257.1 1449643 1450673 − 1031 6 IX87_RS07460 NZ_CP009257.1 1458278 1459507 − 1230 6 IX87_RS07920 NZ_CP009257.1 1536780 1537658 − 879 6 IX87_RS08340 NZ_CP009257.1 1603751 1606126 − 2376 6 IX87_RS08345 NZ_CP009257.1 1606128 1607627 − 1500 6 IX87_RS08385 NZ_CP009257.1 1614377 1615450 − 1074 6 IX87_RS08480 NZ_CP009257.1 1640472 1642319 − 1848 6 IX87_RS23050 NZ_CP009257.1 1646337 1646513 − 177 6 IX87_RS08600 NZ_CP009257.1 1667891 1668658 − 768 6 IX87_RS08825 NZ_CP009257.1 1718628 1719119 + 492 6 IX87_RS09000 NZ_CP009257.1 1758942 1759352 − 411 6 IX87_RS09025 NZ_CP009257.1 1761964 1762608 − 645 6 IX87_RS09030 NZ_CP009257.1 1762615 1763340 − 726 6 IX87_RS09050 NZ_CP009257.1 1765330 1766022 − 693 6 IX87_RS09235 NZ_CP009257.1 1801449 1801901 + 453 6 IX87_RS09285 NZ_CP009257.1 1809057 1811492 − 2436 6 IX87_RS09340 NZ_CP009257.1 1821286 1823718 − 2433 6 IX87_RS09355 NZ_CP009257.1 1825965 1826873 − 909 6 IX87_RS23120 NZ_CP009257.1 1828601 1828747 + 147 6 IX87_RS09725 NZ_CP009257.1 1914838 1915680 − 843 6 IX87_RS09795 NZ_CP009257.1 1929655 1930005 − 351 6 IX87_RS09915 NZ_CP009257.1 1971474 1971680 − 207 6 IX87_RS10115 NZ_CP009257.1 2014671 2015891 − 1221 6 IX87_RS10570 NZ_CP009257.1 2091003 2091938 − 936 6 IX87_RS10655 NZ_CP009257.1 2105509 2106417 + 909 6 IX87_RS10735 NZ_CP009257.1 2125104 2125553 − 450 6 IX87_RS10890 NZ_CP009257.1 2160019 2160273 + 255 6 IX87_RS10985 NZ_CP009257.1 2177848 2178723 + 876 6 IX87_RS10995 NZ_CP009257.1 2179765 2180277 − 513 6 IX87_RS11025 NZ_CP009257.1 2185847 2186377 − 531 6 IX87_RS11065 NZ_CP009257.1 2196414 2196896 + 483 6 IX87_RS11235 NZ_CP009257.1 2228983 2229552 + 570 6 IX87_RS11550 NZ_CP009257.1 2289813 2290418 + 606 6 IX87_RS11705 NZ_CP009257.1 2320232 2320798 − 567 6 IX87_RS12290 NZ_CP009257.1 2425568 2426344 − 777 6 IX87_RS12505 NZ_CP009257.1 2470105 2470674 − 570 6 IX87_RS12580 NZ_CP009257.1 2487196 2488161 − 966 6 IX87_RS12825 NZ_CP009257.1 2533487 2533729 − 243 6 IX87_RS13000 NZ_CP009257.1 2562690 2563433 − 744 6 IX87_RS13015 NZ_CP009257.1 2565605 2566852 + 1248 6 IX87_RS13090 NZ_CP009257.1 2582132 2583004 − 873 6 IX87_RS13255 NZ_CP009257.1 2620660 2621202 + 543 6 IX87_RS13345 NZ_CP009257.1 2639019 2641184 + 2166 6 IX87_RS13635 NZ_CP009257.1 2703079 2703750 + 672 6 IX87_RS13740 NZ_CP009257.1 2723952 2725778 − 1827 6 IX87_RS13900 NZ_CP009257.1 2758137 2759171 + 1035 6 IX87_RS13980 NZ_CP009257.1 2773643 2774743 − 1101 6 IX87_RS13985 NZ_CP009257.1 2774893 2775516 + 624 6 IX87_RS14275 NZ_CP009257.1 2837985 2838371 − 387 6 IX87_RS14305 NZ_CP009257.1 2844627 2845493 + 867 6 IX87_RS14310 NZ_CP009257.1 2845885 2846115 + 231 6 IX87_RS14775 NZ_CP009257.1 2947064 2947945 − 882 6 IX87_RS14805 NZ_CP009257.1 2954208 2955233 + 1026 6 IX87_RS14860 NZ_CP009257.1 2968746 2972396 + 3651 6 IX87_RS15075 NZ_CP009257.1 3009005 3009655 + 651 6 IX87_RS15095 NZ_CP009257.1 3012844 3013998 − 1155 6 IX87_RS15155 NZ_CP009257.1 3025514 3026056 + 543 6 IX87_RS15165 NZ_CP009257.1 3027318 3027926 − 609 6 IX87_RS15335 NZ_CP009257.1 3062236 3062694 + 459 6 IX87_RS15795 NZ_CP009257.1 3154296 3155090 + 795 6 IX87_RS15810 NZ_CP009257.1 3156770 3157381 + 612 6 IX87_RS16140 NZ_CP009257.1 3233266 3233910 + 645 6 IX87_RS16145 NZ_CP009257.1 3233907 3234101 − 195 6 IX87_RS16370 NZ_CP009257.1 3277821 3279074 − 1254 6 IX87_RS16375 NZ_CP009257.1 3279143 3280507 − 1365 6 IX87_RS16440 NZ_CP009257.1 3295397 3296155 + 759 6 IX87_RS16595 NZ_CP009257.1 3320762 3322942 − 2181 6 IX87_RS16745 NZ_CP009257.1 3359883 3361181 + 1299 6 IX87_RS16970 NZ_CP009257.1 3407337 3408230 + 894 6 IX87_RS17140 NZ_CP009257.1 3442151 3443401 − 1251 6 IX87_RS17350 NZ_CP009257.1 3485863 3487218 − 1356 6 IX87_RS17395 NZ_CP009257.1 3497162 3497689 + 528 6 IX87_RS18005 NZ_CP009257.1 3625617 3626810 + 1194 6 IX87_RS18675 NZ_CP009257.1 3743848 3745053 − 1206 6 IX87_RS18710 NZ_CP009257.1 3752760 3754199 + 1440 6 IX87_RS18720 NZ_CP009257.1 3756062 3757972 + 1911 6 IX87_RS18840 NZ_CP009257.1 3782447 3784204 + 1758 6 IX87_RS18870 NZ_CP009257.1 3788682 3789788 − 1107 6 IX87_RS18920 NZ_CP009257.1 3794949 3796034 − 1086 6 IX87_RS18930 NZ_CP009257.1 3797533 3797769 + 237 6 IX87_RS19065 NZ_CP009257.1 3822824 3824095 − 1272 6 IX87_RS19095 NZ_CP009257.1 3829786 3830640 + 855 6 IX87_RS19120 NZ_CP009257.1 3834183 3835916 + 1734 6 IX87_RS19175 NZ_CP009257.1 3846836 3847057 + 222 6 IX87_RS23065 NZ_CP009257.1 3855311 3855556 − 246 6 IX87_RS19420 NZ_CP009257.1 3899229 3899816 + 588 6 IX87_RS19490 NZ_CP009257.1 3913584 3913958 − 375 6 IX87_RS19530 NZ_CP009257.1 3920822 3921196 − 375 6 IX87_RS19800 NZ_CP009257.1 3979780 3980853 + 1074 6 IX87_RS20470 NZ_CP009257.1 4111960 4114389 − 2430 6 IX87_RS20595 NZ_CP009257.1 4139158 4139718 + 561 6 IX87_RS21110 NZ_CP009257.1 4228285 4228500 + 216 6 IX87_RS21210 NZ_CP009257.1 4247592 4248074 + 483 6 IX87_RS21415 NZ_CP009257.1 4284663 4286936 − 2274 6 IX87_RS21425 NZ_CP009257.1 4287713 4290493 − 2781 6 IX87_RS21435 NZ_CP009257.1 4292147 4294681 − 2535 6 IX87_RS01790 NZ_CP009257.1 337140 337700 + 561 5 IX87_RS01830 NZ_CP009257.1 345673 347325 − 1653 5 IX87_RS02350 NZ_CP009257.1 433585 434265 + 681 5 IX87_RS03250 NZ_CP009257.1 608474 608791 + 318 5 IX87_RS03630 NZ_CP009257.1 694138 695346 − 1209 5 IX87_RS03825 NZ_CP009257.1 735701 736468 − 768 5 IX87_RS03830 NZ_CP009257.1 736471 737430 − 960 5 IX87_RS04620 NZ_CP009257.1 901559 901876 − 318 5 IX87_RS05210 NZ_CP009257.1 1003285 1004196 + 912 5 IX87_RS06055 NZ_CP009257.1 1158349 1158783 + 435 5 IX87_RS06405 NZ_CP009257.1 1233238 1233681 + 444 5 IX87_RS06985 NZ_CP009257.1 1358149 1358475 + 327 5 IX87_RS07725 NZ_CP009257.1 1497016 1497951 + 936 5 IX87_RS08475 NZ_CP009257.1 1638371 1640401 + 2031 5 IX87_RS08785 NZ_CP009257.1 1709094 1709726 − 633 5 IX87_RS09220 NZ_CP009257.1 1798775 1800109 + 1335 5 IX87_RS09505 NZ_CP009257.1 1861272 1862054 + 783 5 IX87_RS09580 NZ_CP009257.1 1875038 1875532 − 495 5 IX87_RS10095 NZ_CP009257.1 2008941 2010275 − 1335 5 IX87_RS10490 NZ_CP009257.1 2075682 2076173 − 492 5 IX87_RS10565 NZ_CP009257.1 2089570 2090805 − 1236 5 IX87_RS10955 NZ_CP009257.1 2171849 2172373 + 525 5 IX87_RS11140 NZ_CP009257.1 2210598 2211488 + 891 5 IX87-RS11165 NZ_CP009257.1 2215094 2215984 − 891 5 IX87_RS12275 NZ_CP009257.1 2423072 2423956 + 885 5 IX87_RS12470 NZ_CP009257.1 2463128 2463988 − 861 5 IX87_RS12985 NZ_CP009257.1 2560212 2561114 + 903 5 IX87_RS13175 NZ_CP009257.1 2598888 2599490 − 603 5 IX87_RS13290 NZ_CP009257.1 2628393 2628695 − 303 5 IX87_RS14475 NZ_CP009257.1 2876898 2878040 + 1143 5 IX87_RS15315 NZ_CP009257.1 3058224 3059711 − 1488 5 IX87_RS15355 NZ_CP009257.1 3065845 3066063 − 219 5 IX87_RS16050 NZ_CP009257.1 3214230 3214559 − 330 5 IX87_RS16200 NZ_CP009257.1 3243998 3244414 − 417 5 IX87_RS17520 NZ_CP009257.1 3519159 3520388 + 1230 5 IX87_RS17720 NZ_CP009257.1 3563636 3564466 − 831 5 IX87_RS22945 NZ_CP009257.1 3587332 3587502 + 171 5 IX87_RS18020 NZ_CP009257.1 3629503 3630237 + 735 5 IX87_RS18575 NZ_CP009257.1 3723169 3723951 + 783 5 IX87_RS19130 NZ_CP009257.1 3836202 3837632 + 1431 5 IX87_RS19170 NZ_CP009257.1 3846559 3846744 + 186 5 IX87_RS19395 NZ_CP009257.1 3895311 3895595 + 285 5 IX87_RS19405 NZ_CP009257.1 3896763 3897815 + 1053 5 IX87_RS19810 NZ_CP009257.1 3982048 3983076 − 1029 5 IX87_RS19955 NZ_CP009257.1 4009604 4010371 − 768 5 IX87_RS20040 NZ_CP009257.1 4027179 4028966 + 1788 5 IX87_RS20490 NZ_CP009257.1 4118218 4118847 − 630 5 IX87_RS20495 NZ_CP009257.1 4118862 4119587 − 726 5 IX87_RS20530 NZ_CP009257.1 4125461 4126132 − 672 5 IX87_RS20535 NZ_CP009257.1 4126482 4127198 − 717 5 IX87_RS21320 NZ_CP009257.1 4270344 4270835 − 492 5 IX87_RS21365 NZ_CP009257.1 4276772 4277056 + 285 5 IX87_RS00430 NZ_CP009257.1 61013 61321 + 309 4 IX87_RS00605 NZ_CP009257.1 98347 100023 + 1677 4 IX87_RS22750 NZ_CP009257.1 101137 101301 + 165 4 IX87_RS00695 NZ_CP009257.1 122017 123315 + 1299 4 IX87_RS00725 NZ_CP009257.1 129505 130329 − 825 4 IX87_RS00790 NZ_CP009257.1 140000 140404 − 405 4 IX87_RS00885 NZ_CP009257.1 161396 162274 + 879 4 IX87_RS01565 NZ_CP009257.1 290463 291368 − 906 4 IX87_RS01585 NZ_CP009257.1 293376 294644 + 1269 4 IX87_RS01600 NZ_CP009257.1 299241 300308 + 1068 4 IX87_RS01605 NZ_CP009257.1 300336 301454 + 1119 4 IX87_RS01700 NZ_CP009257.1 317191 317811 − 621 4 IX87_RS01725 NZ_CP009257.1 323939 324394 − 456 4 IX87_RS01815 NZ_CP009257.1 342013 343464 − 1452 4 IX87_RS01840 NZ_CP009257.1 348562 349542 + 981 4 IX87_RS02120 NZ_CP009257.1 392315 393274 − 960 4 IX87_RS02135 NZ_CP009257.1 395818 396792 + 975 4 IX87_RS02245 NZ_CP009257.1 412506 413267 − 762 4 IX87_RS23030 NZ_CP009257.1 455917 456057 − 141 4 IX87_RS02875 NZ_CP009257.1 533496 535370 − 1875 4 IX87_RS02895 NZ_CP009257.1 538135 538884 − 750 4 IX87_RS03050 NZ_CP009257.1 569412 570005 − 594 4 IX87_RS03090 NZ_CP009257.1 576125 577045 − 921 4 IX87_RS03150 NZ_CP009257.1 586874 587740 − 867 4 IX87_RS03205 NZ_CP009257.1 599059 599670 − 612 4 IX87_RS03210 NZ_CP009257.1 599953 600189 + 237 4 IX87_RS03285 NZ_CP009257.1 612173 613078 − 906 4 IX87_RS03690 NZ_CP009257.1 708069 709649 + 1581 4 IX87_RS03695 NZ_CP009257.1 709808 711097 + 1290 4 IX87_RS03735 NZ_CP009257.1 717720 718655 − 936 4 IX87_RS03800 NZ_CP009257.1 729197 730003 − 807 4 IX87_RS03810 NZ_CP009257.1 731402 732496 − 1095 4 IX87_RS04140 NZ_CP009257.1 804543 805847 − 1305 4 IX87_RS04150 NZ_CP009257.1 807340 808272 − 933 4 IX87_RS04165 NZ_CP009257.1 811239 811706 + 468 4 IX87_RS04355 NZ_CP009257.1 844207 845469 + 1263 4 IX87_RS04395 NZ_CP009257.1 849860 852331 − 2472 4 IX87_RS04400 NZ_CP009257.1 852498 852698 + 201 4 IX87_RS04470 NZ_CP009257.1 865642 866835 + 1194 4 IX87_RS04595 NZ_CP009257.1 897308 897733 − 426 4 IX87_RS05015 NZ_CP009257.1 959318 959875 + 558 4 IX87_RS05065 NZ_CP009257.1 970168 971001 + 834 4 IX87_RS05085 NZ_CP009257.1 974697 976184 + 1488 4 IX87_RS05275 NZ_CP009257.1 1016197 1017657 + 1461 4 IX87_RS05295 NZ_CP009257.1 1020490 1021584 − 1095 4 IX87_RS05340 NZ_CP009257.1 1030612 1031970 + 1359 4 IX87_RS05585 NZ_CP009257.1 1085242 1085883 − 642 4 IX87_RS05600 NZ_CP009257.1 1086866 1088098 − 1233 4 IX87_RS06015 NZ_CP009257.1 1148484 1149821 + 1338 4 IX87_RS06060 NZ_CP009257.1 1158832 1161060 − 2229 4 IX87_RS06105 NZ_CP009257.1 1172016 1172909 + 894 4 IX87_RS06130 NZ_CP009257.1 1176695 1177414 − 720 4 IX87_RS06200 NZ_CP009257.1 1191055 1191438 − 384 4 IX87_RS06250 NZ_CP009257.1 1200847 1201344 + 498 4 IX87_RS06270 NZ_CP009257.1 1203470 1204156 − 687 4 IX87_RS06520 NZ_CP009257.1 1261430 1263469 − 2040 4 IX87_RS06570 NZ_CP009257.1 1273122 1274150 + 1029 4 IX87_RS06590 NZ_CP009257.1 1277217 1278119 + 903 4 IX87_RS06605 NZ_CP009257.1 1279612 1280616 + 1005 4 IX87_RS06610 NZ_CP009257.1 1280763 1281326 + 564 4 IX87_RS06860 NZ_CP009257.1 1335895 1336797 − 903 4 IX87_RS06955 NZ_CP009257.1 1351437 1352135 − 699 4 IX87_RS06970 NZ_CP009257.1 1354783 1355931 + 1149 4 IX87_RS06975 NZ_CP009257.1 1356089 1356925 + 837 4 IX87_RS07010 NZ_CP009257.1 1360973 1361767 − 795 4 IX87_RS07130 NZ_CP009257.1 1389541 1390344 − 804 4 IX87_RS07200 NZ_CP009257.1 1404574 1405053 − 480 4 IX87_RS07265 NZ_CP009257.1 1413742 1414365 − 624 4 IX87_RS07345 NZ_CP009257.1 1432682 1433581 − 900 4 IX87_RS07355 NZ_CP009257.1 1433954 1435312 − 1359 4 IX87_RS07360 NZ_CP009257.1 1435309 1435971 − 663 4 IX87_RS07365 NZ_CP009257.1 1436079 1436438 − 360 4 IX87_RS07370 NZ_CP009257.1 1436520 1438277 − 1758 4 IX87_RS07375 NZ_CP009257.1 1438565 1439833 + 1269 4 IX87_RS07380 NZ_CP009257.1 1439843 1440571 − 729 4 IX87_RS07390 NZ_CP009257.1 1441510 1442379 − 870 4 IX87_RS07430 NZ_CP009257.1 1448683 1449468 − 786 4 IX87_RS07730 NZ_CP009257.1 1497948 1498721 + 774 4 IX87_RS07925 NZ_CP009257.1 1537655 1538164 − 510 4 IX87_RS08455 NZ_CP009257.1 1634109 1635077 − 969 4 IX87_RS08500 NZ_CP009257.1 1645659 1646345 + 687 4 IX87_RS08515 NZ_CP009257.1 1648046 1649026 − 981 4 IX87_RS08755 NZ_CP009257.1 1703440 1704078 − 639 4 IX87_RS08770 NZ_CP009257.1 1706318 1706929 − 612 4 IX87_RS08810 NZ_CP009257.1 1715712 1716593 − 882 4 IX87_RS08915 NZ_CP009257.1 1741284 1742309 − 1026 4 IX87_RS09005 NZ_CP009257.1 1759538 1759975 + 438 4 IX87_RS09035 NZ_CP009257.1 1763354 1764067 − 714 4 IX87_RS09100 NZ_CP009257.1 1775397 1776209 − 813 4 IX87_RS09110 NZ_CP009257.1 1777511 1778119 + 609 4 IX87_RS09430 NZ_CP009257.1 1844447 1845334 − 888 4 IX87_RS09485 NZ_CP009257.1 1855753 1856544 − 792 4 IX87_RS09495 NZ_CP009257.1 1859427 1860593 + 1167 4 IX87_RS09565 NZ_CP009257.1 1869643 1873641 − 3999 4 IX87_RS09670 NZ_CP009257.1 1905970 1907478 − 1509 4 IX87_RS10045 NZ_CP009257.1 1997531 1997965 − 435 4 IX87_RS22855 NZ_CP009257.1 2093718 2093858 − 141 4 IX87_RS10650 NZ_CP009257.1 2105036 2105404 − 369 4 IX87_RS10725 NZ_CP009257.1 2124170 2124514 − 345 4 IX87_RS10780 NZ_CP009257.1 2134246 2134536 + 291 4 IX87_RS11325 NZ_CP009257.1 2243938 2244834 − 897 4 IX87_RS11385 NZ_CP009257.1 2257011 2258021 − 1011 4 IX87_RS11480 NZ_CP009257.1 2275098 2276024 − 927 4 IX87_RS11615 NZ_CP009257.1 2302131 2302754 − 624 4 IX87_RS11660 NZ_CP009257.1 2311147 2311740 − 594 4 IX87_RS12440 NZ_CP009257.1 2458260 2458472 − 213 4 IX87_RS12510 NZ_CP009257.1 2470686 2472851 − 2166 4 IX87_RS12515 NZ_CP009257.1 2472914 2473441 − 528 4 IX87_RS12520 NZ_CP009257.1 2473452 2474192 − 741 4 IX87_RS12525 NZ_CP009257.1 2474189 2474830 − 642 4 IX87_RS12730 NZ_CP009257.1 2520900 2521331 + 432 4 IX87_RS12795 NZ_CP009257.1 2528229 2528858 − 630 4 IX87_RS12800 NZ_CP009257.1 2528871 2529821 − 951 4 IX87_RS13185 NZ_CP009257.1 2602655 2604361 − 1707 4 IX87_RS13330 NZ_CP009257.1 2637108 2637905 − 798 4 IX87_RS13350 NZ_CP009257.1 2641243 2641818 − 576 4 IX87_RS13525 NZ_CP009257.1 2678294 2679019 + 726 4 IX87_RS13770 NZ_CP009257.1 2733252 2733791 − 540 4 IX87_RS13775 NZ_CP009257.1 2733824 2734576 − 753 4 IX87_RS13785 NZ_CP009257.1 2736075 2737340 − 1266 4 IX87_RS13925 NZ_CP009257.1 2761671 2763095 − 1425 4 IX87_RS14045 NZ_CP009257.1 2790856 2791433 − 578 4 IX87_RS14180 NZ_CP009257.1 2821253 2821951 + 699 4 IX87_RS14225 NZ_CP009257.1 2828269 2828634 − 366 4 IX87_RS14250 NZ_CP009257.1 2833765 2834127 + 363 4 IX87_RS14260 NZ_CP009257.1 2834311 2834823 + 513 4 IX87_RS14485 NZ_CP009257.1 2879204 2881372 + 2169 4 IX87_RS14735 NZ_CP009257.1 2936888 2938852 − 1965 4 IX87_RS14855 NZ_CP009257.1 2964762 2968721 + 3960 4 IX87_RS14940 NZ_CP009257.1 2985288 2985815 + 528 4 IX87_RS15065 NZ_CP009257.1 3006868 3007632 − 765 4 IX87_RS15300 NZ_CP009257.1 3054994 3055872 − 879 4 IX87_RS15510 NZ_CP009257.1 3097157 3098062 + 906 4 IX87_RS15730 NZ_CP009257.1 3141650 3142408 + 759 4 IX87_RS15865 NZ_CP009257.1 3167744 3168658 + 915 4 IX87_RS16215 NZ_CP009257.1 3246651 3247547 + 897 4 IX87_RS16250 NZ_CP009257.1 3255783 3256478 + 696 4 IX87_RS16480 NZ_CP009257.1 3302512 3302667 − 156 4 IX87_RS16585 NZ_CP009257.1 3317401 3318171 + 771 4 IX87_RS16730 NZ_CP009257.1 3355181 3356023 − 843 4 IX87_RS16750 NZ_CP009257.1 3361206 3361757 + 552 4 IX87_RS16875 NZ_CP009257.1 3386424 3386753 − 330 4 IX87_RS17005 NZ_CP009257.1 3414219 3414533 + 315 4 IX87_RS17065 NZ_CP009257.1 3428699 3429472 − 774 4 IX87_RS17070 NZ_CP009257.1 3429584 3430390 + 807 4 IX87_RS17115 NZ_CP009257.1 3436284 3437912 − 1629 4 IX87_RS17215 NZ_CP009257.1 3455928 3457331 + 1404 4 IX87_RS17325 NZ_CP009257.1 3481112 3481363 + 252 4 IX87_RS17355 NZ_CP009257.1 3487576 3488418 + 843 4 IX87_RS17360 NZ_CP009257.1 3488719 3489552 + 834 4 IX87_RS17385 NZ_CP009257.1 3495850 3496398 − 549 4 IX87_RS17440 NZ_CP009257.1 3504555 3506489 + 1935 4 IX87_RS17870 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892810 − 417 3 IX87_RS06035 NZ_CP009257.1 1153864 1154898 − 1035 3 IX87_RS06115 NZ_CP009257.1 1174102 1174752 + 651 3 IX87_RS06160 NZ_CP009257.1 1183037 1184623 + 1587 3 IX87_RS06165 NZ_CP009257.1 1184697 1184921 − 225 3 IX87_RS22815 NZ_CP009257.1 1186438 1186569 − 132 3 IX87_RS06335 NZ_CP009257.1 1220410 1221225 + 816 3 IX87_RS06615 NZ_CP009257.1 1281366 1281830 − 465 3 IX87_RS06800 NZ_CP009257.1 1322781 1323233 − 453 3 IX87_RS22130 NZ_CP009257.1 1339112 1339234 + 123 3 IX87_RS07180 NZ_CP009257.1 1399351 1401240 − 1890 3 IX87_RS07325 NZ_CP009257.1 1428329 1428601 − 273 3 IX87_RS07465 NZ_CP009257.1 1459757 1460443 + 687 3 IX87_RS08485 NZ_CP009257.1 1642714 1643574 + 861 3 IX87_RS09085 NZ_CP009257.1 1773161 1773577 − 417 3 IX87_RS09550 NZ_CP009257.1 1868079 1868498 − 420 3 IX87_RS10100 NZ_CP009257.1 2010301 2010975 − 675 3 IX87_RS10535 NZ_CP009257.1 2084143 2084892 + 750 3 IX87_RS10685 NZ_CP009257.1 2115210 2115746 − 537 3 IX87_RS10695 NZ_CP009257.1 2116193 2116576 − 384 3 IX87_RS10730 NZ_CP009257.1 2124606 2124962 − 357 3 IX87_RS23055 NZ_CP009257.1 2143160 2143303 + 144 3 IX87_RS11310 NZ_CP009257.1 2242542 2243036 + 495 3 IX87_RS11470 NZ_CP009257.1 2272274 2273431 − 1158 3 IX87_RS11490 NZ_CP009257.1 2278022 2278621 + 600 3 IX87_RS11760 NZ_CP009257.1 2329396 2329512 − 117 3 IX87_RS12200 NZ_CP009257.1 2408277 2408744 − 468 3 IX87_RS12300 NZ_CP009257.1 2427423 2428457 + 1035 3 IX87_RS12765 NZ_CP009257.1 2524371 2525012 + 642 3 IX87_RS14715 NZ_CP009257.1 2934471 2935172 + 702 3 IX87_RS14935 NZ_CP009257.1 2984279 2985067 + 789 3 IX87_RS15785 NZ_CP009257.1 3151712 3152242 + 531 3 IX87_RS15875 NZ_CP009257.1 3169253 3170113 − 861 3 IX87_RS16415 NZ_CP009257.1 3290260 3290505 + 246 3 IX87_RS16570 NZ_CP009257.1 3315674 3316036 − 363 3 IX87_RS17265 NZ_CP009257.1 3469020 3469397 − 378 3 IX87_RS22940 NZ_CP009257.1 3492449 3493825 + 1377 3 IX87_RS17400 NZ_CP009257.1 3497822 3498487 + 666 3 IX87_RS18715 NZ_CP009257.1 3754211 3756052 + 1842 3 IX87_RS20275 NZ_CP009257.1 4071722 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IX87_RS02145 NZ_CP009257.1 397655 398251 + 597 2 IX87_RS02235 NZ_CP009257.1 411161 411502 − 342 2 IX87_RS02340 NZ_CP009257.1 431645 431953 + 309 2 IX87_RS02460 NZ_CP009257.1 456424 456609 + 186 2 IX87_RS02480 NZ_CP009257.1 459068 459661 − 594 2 IX87_RS02515 NZ_CP009257.1 465225 465761 + 537 2 IX87_RS02535 NZ_CP009257.1 467813 470350 + 2538 2 IX87_RS02545 NZ_CP009257.1 471943 472122 + 180 2 IX87_RS02550 NZ_CP009257.1 472162 473013 − 852 2 IX87_RS02575 NZ_CP009257.1 476867 477766 + 900 2 IX87_RS02630 NZ_CP009257.1 483670 484215 + 546 2 IX87_RS02700 NZ_CP009257.1 497040 497870 + 831 2 IX87_RS02725 NZ_CP009257.1 501669 502190 − 522 2 IX87_RS02850 NZ_CP009257.1 530235 531137 + 903 2 IX87_RS02915 NZ_CP009257.1 542440 543309 − 870 2 IX87_RS02985 NZ_CP009257.1 558048 558965 + 918 2 IX87_RS03030 NZ_CP009257.1 564641 566320 − 1680 2 IX87_RS03075 NZ_CP009257.1 573542 574447 + 906 2 IX87_RS03180 NZ_CP009257.1 591475 592434 − 960 2 IX87_RS03190 NZ_CP009257.1 596061 597707 + 1647 2 IX87_RS03195 NZ_CP009257.1 597764 598219 − 456 2 IX87_RS03215 NZ_CP009257.1 600250 601485 − 1236 2 IX87_RS03255 NZ_CP009257.1 608876 609097 − 222 2 IX87_RS03260 NZ_CP009257.1 609185 609466 − 282 2 IX87_RS03495 NZ_CP009257.1 666641 667678 − 1038 2 IX87_RS03510 NZ_CP009257.1 670023 670838 + 816 2 IX87_RS03615 NZ_CP009257.1 691197 691802 − 606 2 IX87_RS03770 NZ_CP009257.1 724271 725449 − 1179 2 IX87_RS03780 NZ_CP009257.1 725947 726594 − 648 2 IX87_RS03785 NZ_CP009257.1 726767 727618 + 852 2 IX87_RS03790 NZ_CP009257.1 727621 728574 − 954 2 IX87_RS03795 NZ_CP009257.1 728582 729184 − 603 2 IX87_RS03880 NZ_CP009257.1 750406 750807 + 402 2 IX87_RS03930 NZ_CP009257.1 757712 758248 + 537 2 IX87_RS03935 NZ_CP009257.1 758288 761893 − 3606 2 IX87_RS04015 NZ_CP009257.1 777353 778264 − 912 2 IX87_RS04085 NZ_CP009257.1 795801 796499 + 699 2 IX87_RS04145 NZ_CP009257.1 806112 806753 − 642 2 IX87_RS04160 NZ_CP009257.1 810259 811119 − 861 2 IX87_RS04210 NZ_CP009257.1 819961 821151 − 1191 2 IX87_RS04215 NZ_CP009257.1 821148 823289 − 2142 2 IX87_RS04325 NZ_CP009257.1 841072 841617 − 546 2 IX87_RS04330 NZ_CP009257.1 841655 842044 − 390 2 IX87_RS04385 NZ_CP009257.1 848948 849355 − 408 2 IX87_RS04390 NZ_CP009257.1 849383 849784 − 402 2 IX87_RS04445 NZ_CP009257.1 860567 861526 − 960 2 IX87_RS04475 NZ_CP009257.1 867303 868661 + 1359 2 IX87_RS04510 NZ_CP009257.1 877140 877358 − 219 2 IX87_RS04655 NZ_CP009257.1 911427 912071 + 645 2 IX87_RS04660 NZ_CP009257.1 912186 912680 + 495 2 IX87_RS04820 NZ_CP009257.1 939842 940483 − 642 2 IX87_RS05060 NZ_CP009257.1 969146 970105 + 960 2 IX87_RS05070 NZ_CP009257.1 971025 972548 + 1524 2 IX87_RS05080 NZ_CP009257.1 973547 974560 − 1014 2 IX87_RS05160 NZ_CP009257.1 992666 993505 + 840 2 IX87_RS05225 NZ_CP009257.1 1006834 1007589 − 756 2 IX87_RS05235 NZ_CP009257.1 1008410 1009018 − 609 2 IX87_RS05245 NZ_CP009257.1 1010733 1012280 + 1548 2 IX87_RS05330 NZ_CP009257.1 1027670 1029001 + 1332 2 IX87_RS05590 NZ_CP009257.1 1085949 1086350 + 402 2 IX87_RS05595 NZ_CP009257.1 1086405 1086656 − 252 2 IX87_RS05985 NZ_CP009257.1 1143190 1143459 + 270 2 IX87_RS05990 NZ_CP009257.1 1143465 1144727 − 1263 2 IX87_RS06190 NZ_CP009257.1 1188167 1190323 − 2157 2 IX87_RS06210 NZ_CP009257.1 1192083 1192553 − 471 2 IX87_RS06260 NZ_CP009257.1 1202008 1202691 − 684 2 IX87_RS06325 NZ_CP009257.1 1217563 1218999 + 1437 2 IX87_RS06395 NZ_CP009257.1 1231842 1232720 + 879 2 IX87_RS06435 NZ_CP009257.1 1237552 1237953 − 402 2 IX87_RS06440 NZ_CP009257.1 1238209 1239408 + 1200 2 IX87_RS06445 NZ_CP009257.1 1239434 1240417 − 984 2 IX87_RS06450 NZ_CP009257.1 1240556 1240990 − 435 2 IX87_RS06535 NZ_CP009257.1 1265843 1266223 − 381 2 IX87_RS06600 NZ_CP009257.1 1278974 1279477 + 504 2 IX87_RS06790 NZ_CP009257.1 1320816 1321382 − 567 2 IX87_RS06895 NZ_CP009257.1 1342847 1345345 − 2499 2 IX87_RS06915 NZ_CP009257.1 1347316 1347852 − 537 2 IX87_RS06960 NZ_CP009257.1 1352232 1353134 + 903 2 IX87_RS06995 NZ_CP009257.1 1359106 1359468 − 363 2 IX87_RS07005 NZ_CP009257.1 1360399 1360998 − 600 2 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NZ_CP009257.1 1750012 1750959 − 948 2 IX87_RS09010 NZ_CP009257.1 1759990 1760469 − 480 2 IX87_RS09055 NZ_CP009257.1 1765994 1766368 − 375 2 IX87_RS09410 NZ_CP009257.1 1837533 1839179 + 1647 2 IX87_RS09435 NZ_CP009257.1 1845497 1846120 + 624 2 IX87_RS09470 NZ_CP009257.1 1853098 1854072 − 975 2 IX87_RS09475 NZ_CP009257.1 1854069 1855136 − 1068 2 IX87_RS09480 NZ_CP009257.1 1855241 1855633 − 393 2 IX87_RS09500 NZ_CP009257.1 1860582 1861148 − 567 2 IX87_RS09610 NZ_CP009257.1 1881184 1881759 − 576 2 IX87_RS09620 NZ_CP009257.1 1885191 1886333 + 1143 2 IX87_RS09630 NZ_CP009257.1 1887447 1887821 + 375 2 IX87_RS09780 NZ_CP009257.1 1926810 1927139 − 330 2 IX87_RS09955 NZ_CP009257.1 1979314 1979694 + 381 2 IX87_RS10075 NZ_CP009257.1 2004693 2005598 − 906 2 IX87_RS10105 NZ_CP009257.1 2010990 2012639 − 1650 2 IX87_RS10485 NZ_CP009257.1 2075134 2075694 − 561 2 IX87_RS10660 NZ_CP009257.1 2106516 2106659 + 144 2 IX87_RS10700 NZ_CP009257.1 2116898 2117497 + 600 2 IX87_RS10755 NZ_CP009257.1 2128390 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IX87_RS12355 NZ_CP009257.1 2438494 2439054 − 561 2 IX87_RS12425 NZ_CP009257.1 2450771 2451658 − 888 2 IX87_RS12530 NZ_CP009257.1 2474830 2475852 − 1023 2 IX87_RS12570 NZ_CP009257.1 2485718 2486050 − 333 2 IX87_RS12660 NZ_CP009257.1 2503088 2503414 − 327 2 IX87_RS12810 NZ_CP009257.1 2530734 2531372 − 639 2 IX87_RS12815 NZ_CP009257.1 2531482 2532486 + 1005 2 IX87_RS12960 NZ_CP009257.1 2556489 2556707 + 219 2 IX87_RS12990 NZ_CP009257.1 2561226 2562227 + 1002 2 IX87_RS13010 NZ_CP009257.1 2564546 2565466 − 921 2 IX87_RS13130 NZ_CP009257.1 2591825 2592520 + 696 2 IX87_RS13165 NZ_CP009257.1 2597488 2597841 − 354 2 IX87_RS13250 NZ_CP009257.1 2620141 2620554 − 414 2 IX87_RS13275 NZ_CP009257.1 2625141 2625848 − 708 2 IX87_RS13355 NZ_CP009257.1 2642067' 2642339 − 273 2 IX87_RS13420 NZ_CP009257.1 2658176 2658388 + 213 2 IX87_RS13530 NZ_CP009257.1 2679072 2680229 − 1158 2 IX87_RS13535 NZ_CP009257.1 2680429 2681439 + 1011 2 IX87_RS13560 NZ_CP009257.1 2686163 2686519 − 357 2 IX87_RS13570 NZ_CP009257.1 2686998 2687317 + 320 2 IX87_RS13670 NZ_CP009257.1 2710800 2711243 + 444 2 IX87_RS13880 NZ_CP009257.1 2755728 2756186 − 459 2 IX87_RS13905 NZ_CP009257.1 2759219 2759755 + 537 2 IX87_RS13910 NZ_CP009257.1 2759765 2760010 + 246 2 IX87_RS13940 NZ_CP009257.1 2764567 2765370 + 804 2 IX87_RS14105 NZ_CP009257.1 2804249 2805253 − 1005 2 IX87_RS14280 NZ_CP009257.1 2838473 2839378 − 906 2 IX87_RS14300 NZ_CP009257.1 2843591 2844519 − 929 2 IX87_RS14355 NZ_CP009257.1 2854472 2854798 + 327 2 IX87_RS14390 NZ_CP009257.1 2861851 2862417 + 567 2 IX87_RS14415 NZ_CP009257.1 2866143 2867126 − 984 2 IX87_RS14430 NZ_CP009257.1 2869976 2870296 − 321 2 IX87_RS14685 NZ_CP009257.1 2927022 2927597 + 576 2 IX87_RS14705 NZ_CP009257.1 2931641 2932870 + 1230 2 IX87_RS14720 NZ_CP009257.1 2935284 2935949 + 666 2 IX87_RS14740 NZ_CP009257.1 2939054 2940199 + 1146 2 IX87_RS14820 NZ_CP009257.1 2957391 2957807 − 417 2 IX87_RS14865 NZ_CP009257.1 2972393 2973667 + 1275 2 IX87_RS14875 NZ_CP009257.1 2975648 2976340 + 693 2 IX87_RS14920 NZ_CP009257.1 2980543 2980980 + 438 2 IX87_RS15070 NZ_CP009257.1 3007654 3008868 − 1215 2 IX87_RS15120 NZ_CP009257.1 3017633 3018847 − 1215 2 IX87_RS15175 NZ_CP009257.1 3028815 3029300 − 486 2 IX87_RS15180 NZ_CP009257.1 3029382 3029786 + 405 2 IX87_RS15230 NZ_CP009257.1 3039800 3040405 − 606 2 IX87_RS15245 NZ_CP009257.1 3042927 3043571 + 645 2 IX87_RS15295 NZ_CP009257.1 3054124 3054951 + 828 2 IX87_RS15305 NZ_CP009257.1 3055888 3056664 − 777 2 IX87_RS15535 NZ_CP009257.1 3102339 3103478 + 1140 2 IX87_RS15805 NZ_CP009257.1 3155919 3156773 + 855 2 IX87_RS15930 NZ_CP009257.1 3179906 3180307 + 402 2 IX87_RS16025 NZ_CP009257.1 3206094 3207845 + 1752 2 IX87_RS16030 NZ_CP009257.1 3208562 3209860 − 1299 2 IX87_RS16110 NZ_CP009257.1 3227249 3227506 + 258 2 IX87_RS16205 NZ_CP009257.1 3244577 3245731 + 1155 2 IX87_RS16210 NZ_CP009257.1 3245783 3246538 − 756 2 IX87_RS16315 NZ_CP009257.1 3269023 3269271 − 249 2 IX87_RS16560 NZ_CP009257.1 3314155 3314664 − 510 2 IX87_RS16615 NZ_CP009257.1 3324800 3325675 + 876 2 IX87_RS17015 NZ_CP009257.1 3416053 3416874 − 822 2 IX87_RS17260 NZ_CP009257.1 3468422 3468859 − 438 2 IX87_RS17445 NZ_CP009257.1 3506503 3507231 + 729 2 IX87_RS17460 NZ_CP009257.1 3508737 3509216 + 480 2 IX87_RS17500 NZ_CP009257.1 3513881 3515056 + 1176 2 IX87_RS17535 NZ_CP009257.1 3523126 3524055 − 930 2 IX87_RS17545 NZ_CP009257.1 3525074 3526384 − 1311 2 IX87_RS17675 NZ_CP009257.1 3556022 3556156 − 135 2 IX87_RS17685 NZ_CP009257.1 3559377 3559583 + 207 2 IX87_RS17845 NZ_CP009257.1 3587515 3588714 − 1200 2 IX87_RS17940 NZ_CP009257.1 3610367' 3611290 − 924 2 IX87_RS18015 NZ_CP009257.1 3628296 3629147 − 852 2 IX87_RS18205 NZ_CP009257.1 3659788 3660339 + 552 2 IX87_RS18490 NZ_CP009257.1 3703101 3703523 − 423 2 IX87_RS18695 NZ_CP009257.1 3748691 3749155 + 465 2 IX87_RS18765 NZ_CP009257.1 3767339 3767965 + 627 2 IX87_RS18770 NZ_CP009257.1 3767953 3768471 + 519 2 IX87_RS18790 NZ_CP009257.1 3771920 3772663 + 744 2 IX87_RS18800 NZ_CP009257.1 3773945 3774832 − 888 2 IX87_RS18815 NZ_CP009257.1 3776813 3777040 − 228 2 IX87_RS18860 NZ_CP009257.1 3787422 3787883 + 462 2 IX87_RS19060 NZ_CP009257.1 3821843 3822754 − 912 2 IX87_RS19075 NZ_CP009257.1 3824992 3826647 + 1656 2 IX87_RS19140 NZ_CP009257.1 3838523 3839362 + 840 2 IX87_RS19260 NZ_CP009257.1 3862694 3863680 + 987 2 IX87_RS19295 NZ_CP009257.1 3870370 3871428 − 1059 2 IX87_RS19305 NZ_CP009257.1 3872918 3873409 − 492 2 IX87_RS19315 NZ_CP009257.1 3875050 3875400 + 351 2 IX87_RS19330 NZ_CP009257.1 3877071 3877691 + 621 2 IX87_RS19415 NZ_CP009257.1 3898826 3899062 + 237 2 IX87_RS19430 NZ_CP009257.1 3901817 3902284 + 468 2 IX87_RS19900 NZ_CP009257.1 3997189 3997629 + 441 2 IX87_RS19920 NZ_CP009257.1 4000571 4001809 − 1239 2 IX87_RS19950 NZ_CP009257.1 4008136 4009488 − 1353 2 IX87_RS19965 NZ_CP009257.1 4011937 4012821 − 885 2 IX87_RS19985 NZ_CP009257.1 4015182 4015946 − 765 2 IX87_RS20000 NZ_CP009257.1 4018405 4019457 − 1053 2 IX87_RS20335 NZ_CP009257.1 4084321 4085100 + 780 2 IX87_RS20370 NZ_CP009257.1 4093669 4094406 − 738 2 IX87_RS20380 NZ_CP009257.1 4094913 4096190 − 1278 2 IX87_RS20485 NZ_CP009257.1 4117322 4118149 − 828 2 IX87_RS20570 NZ_CP009257.1 4133800 4134597 + 798 2 IX87_RS20690 NZ_CP009257.1 4162078 4162686 + 609 2 IX87_RS20735 NZ_CP009257.1 4168206 4168877 − 672 2 IX87_RS20785 NZ_CP009257.1 4175596 4175919 − 324 2 IX87_RS20815 NZ_CP009257.1 4180715 4181170 − 456 2 IX87_RS21130 NZ_CP009257.1 4233621 4234250 + 630 2 IX87_RS21155 NZ_CP009257.1 4239278 4240024 − 747 2 IX87_RS21360 NZ_CP009257.1 4276404 4276754 + 351 2 IX87_RS21375 NZ_CP009257.1 4277392 4278243 − 852 2 IX87_RS21420 NZ_CP009257.1 4287087 4287716 − 630 2 IX87_RS21485 NZ_CP009257.1 4299933 4300943 + 1011 2 IX87_RS21515 NZ_CP009257.1 4305821 4306984 − 1164 2 IX87_RS00070 NZ_CP009257.1 6580 7008 − 429 1 IX87_RS00950 NZ_CP009257.1 176584 177474 − 891 1 IX87_RS01580 NZ_CP009257.1 292739 293251 − 513 1 IX87_RS01890 NZ_CP009257.1 355224 361472 − 6249 1 IX87_RS02215 NZ_CP009257.1 408790 409170 − 381 1 IX87_RS02220 NZ_CP009257.1 409160 409714 − 555 1 IX87_RS02530 NZ_CP009257.1 467021 467761 + 741 1 IX87_RS02570 NZ_CP009257.1 476340 476777 − 438 1 IX87_RS02870 NZ_CP009257.1 533277 533438 − 162 1 IX87_RS02900 NZ_CP009257.1 539282 540751 + 1470 1 IX87_RS22760 NZ_CP009257.1 556299 556433 + 135 1 IX87_RS03750 NZ_CP009257.1 720754 721041 − 288 1 IX87_RS03885 NZ_CP009257.1 750903 751847 + 945 1 IX87_RS22795 NZ_CP009257.1 756062 756187 − 126 1 IX87_RS04345 NZ_CP009257.1 843468 843701 − 234 1 IX87_RS04715 NZ_CP009257.1 925346 925750 − 405 1 IX87_RS04720 NZ_CP009257.1 925843 926025 − 183 1 IX87_RS05140 NZ_CP009257.1 988872 989816 + 945 1 IX87_RS05145 NZ_CP009257.1 989858 990550 − 693 1 IX87_RS22030 NZ_CP009257.1 1012406 1012627 + 222 1 IX87_RS05825 NZ_CP009257.1 1123748 1124176 − 429 1 IX87_RS06265 NZ_CP009257.1 1202701 1203462 − 762 1 IX87_RS06360 NZ_CP009257.1 1225686 1225904 − 219 1 IX87_RS06990 NZ_CP009257.1 1358472 1358942 − 471 1 IX87_RS08025 NZ_CP009257.1 1560840 1561244 − 405 1 IX87_RS08030 NZ_CP009257.1 1561337 1561519 − 183 1 IX87_RS08895 NZ_CP009257.1 1736769 1737905 − 1137 1 IX87_RS09125 NZ_CP009257.1 1779926 1780987 + 1062 1 IX87_RS09225 NZ_CP009257.1 1800320 1800727 + 408 1 IX87_RS09960 NZ_CP009257.1 1979744 1980217 − 474 1 IX87_RS10785 NZ_CP009257.1 2134547 2134900 − 354 1 IX87_RS11050 NZ_CP009257.1 2191874 2192254 + 381 1 IX87_RS11715 NZ_CP009257.1 2322731 2323120 − 390 1 IX87_RS11875 NZ_CP009257.1 2340277 2341005 − 729 1 IX87_RS12305 NZ_CP009257.1 2428572 2429513 + 942 1 IX87_RS12545 NZ_CP009257.1 2479450 2479782 − 333 1 IX87_RS12645 NZ_CP009257.1 2497265 2500423 − 3159 1 IX87_RS12785 NZ_CP009257.1 2527485 2527796 − 312 1 IX87_RS12790 NZ_CP009257.1 2527803 2528192 − 390 1 IX87_RS13510 NZ_CP009257.1 2675956 2676459 + 504 1 IX87_RS13540 NZ_CP009257.1 2681415 2681939 + 525 1 IX87_RS14000 NZ_CP009257.1 2780047 2780937 + 891 1 IX87_RS14540 NZ_CP009257.1 2892269 2893309 + 1041 1 IX87_RS15090 NZ_CP009257.1 3011693 3012823 − 1131 1 IX87_RS15395 NZ_CP009257.1 3073910 3074341 − 432 1 IX87_RS15450 NZ_CP009257.1 3084892 3085155 + 264 1 IX87_RS16090 NZ_CP009257.1 3223840 3224184 + 345 1 IX87_RS16095 NZ_CP009257.1 3224329 3224667 + 339 1 IX87_RS16165 NZ_CP009257.1 3236746 3237126 + 381 1 IX87_RS16245 NZ_CP009257.1 3255035 3255709 + 675 1 IX87_RS16340 NZ_CP009257.1 3273468 3273875 − 408 1 IX87_RS16345 NZ_CP009257.1 3274044 3274412 + 369 1 IX87_RS16350 NZ_CP009257.1 3274464 3274685 − 222 1 IX87_RS17405 NZ_CP009257.1 3498499 3499290 + 792 1 IX87_RS18780 NZ_CP009257.1 3769521 3770120 + 600 1 IX87_RS19485 NZ_CP009257.1 3913207 3913581 − 375 1 IX87_RS19525 NZ_CP009257.1 3920445 3920819 − 375 1 IX87_RS19705 NZ_CP009257.1 3956110 3956868 − 759 1 IX87_RS20330 NZ_CP009257.1 4083096 4084310 + 1215 1 IX87_RS20520 NZ_CP009257.1 4123565 4124776 − 1212 1 IX87_RS20585 NZ_CP009257.1 4136520 4136927 − 408 1 IX87_RS22670 NZ_CP009257.1 4226744 4226836 + 93 1 IX87_RS21185 NZ_CP009257.1 4244367 4244603 − 237 1 IX87_RS21615 NZ_CP009257.1 4323255 4327616 − 4362 1

Example 13

RNA Sequencing to Identify Bacterial Resistance in Humans with Sepsis

Attached are the bacterial resistance genes identified in one patient with COVID-19. Resistance Gene.

ARO Ontology # of Antibiotic ID Mutation Reads Primary Species Resistance Nucleotide 3002618 aadA21 2 n/a n/a Protein 3001028 TEM-162 2 n/a n/a Homolog 3002884 iri 2 n/a n/a 3001037 TEM-171 2 n/a n/a 3000976 TEM-113 2 n/a n/a 3000167 tet(C) 2 n/a n/a 3000833 evgS 2 n/a n/a 3003548 mdtN 2 n/a n/a 3001023 TEM-157 2 n/a n/a 3002621 aadA24 2 n/a n/a 3002620 aadA23 4 n/a n/a 3000979 TEM-116 4 n/a n/a 3002655 APH(4)-Ia 4 n/a n/a 3002641 APH(3′)-Ia 4 n/a n/a 3002601 aadA 4 n/a n/a 3002619 aadA22 4 n/a n/a 3004089 AND(3″)-IIa 4 n/a n/a 3001044 TEM-181 4 n/a n/a 3005036 BLMT 4 n/a n/a 3000805 OprN 6 n/a n/a 3002644 APH(3′)-IIa 8 n/a n/a Nucleotide 3004114 porin 2 n/a n/a Protein OmpC Knockout Nucleotide n/a n/a n/a n/a n/a Protein Over- expression Nucleotide 3003817 DNA gyrase 2 Acinetobacter Fluoroquinolones Protein 3003974 DNA gyrase 2 Cutibacterium Fluoroquinolones Variant Nucleotide 3005083 23s rRNA 2 Thermus Pleuromutilins rRNA Thermophilus 3004170 23s rRNA 4 Streptococcus Macrolides 3003372 16S rRNA 4 Escherichia Spectinomycin (rrsH) 3003512 16S rRNA 6 Salmonella Spectinomycin (rrsD) 3004836 23S rRNA 6 Neisseria Azithromycin 3004181 23S rRNA 8 Streptococcus Macrolides, streptogramins 3003493 16S rRNA 10 Pasteurella Spectinomycin 3004058 23S rRNA 14 Staphylococcus Linezolid 3004131 23S rRNA 16 Escherichia Macrolides 3004149 23S rRNA 16 Escherichia Clindamycin 3004160 23S rRNA 16 Escherichia Clarithromycin 3004173 23S rRNA 16 Escherichia Oxazolidinone 3004150 23s rRNA 16 Escherichia Chloramphenicol 3003495 16S rRNA 24 Neisseria Spectinomycin 3003499 16S rRNA 24 Cutibacterium Tetracyclines 3004138 23S rRNA 48 Moraxella Macrolides 3004161 23S rRNA 58 Propionibacteria Macrolides 3003480 16S rRNA 98 Mycobacterium Streptomycin 3004853 16S rRNA 98 Mycobacterium Capreomycin 3003436 16S rRNA 98 Mycobacterium Kanamycin 3003437 16S rRNA 98 Mycobacterium Viomycin 3003481 16S rRNA 98 Mycobacterium Amikacin 3004171 23S rRNA 284 Streptomyces Macrolides 3003540 16S rRNA 332 Mycolicibacterium Hygromycin B (rrsB) 3003497 16S rRNA 436 Neisseria Spectinomycin 3003514 16S rRNA 450 Mycobacteroides Amikacin 3003515 16S rRNA 450 Mycobacteroides Kanamycin A 3003516 16S rRNA 450 Mycobacteroides Tobramycin 3003517 16S rRNA 450 Mycobacteroides Gentamicin C 3003518 16S rRNA 450 Mycobacteroides Neomycin 3003541 16S rRNA 452 Mycolicibacterium Streptomycin (rrsB) 3003542 16S rRNA 452 Mycolicibacterium Kanamycin A (rrsB) 3003545 16S rRNA 452 Mycolicibacterium Neomycin (rrsB) 3003547 16S rRNA 452 Mycolicibacterium Viomycin (rrsB) 3003539 16S rRNA 466 Mycolicibacterium Hygromycin B (rrsA) 3003543 16S rRNA 466 Mycolicibacterium Kanamycin A (rrsA) 3003544 16S rRNA 466 Mycolicibacterium Neomycin (rrsA) 3003546 16S rRNA 466 Mycolicibacterium Viomycin (rrsA) 3004164 23S rRNA 580 Mycobacterium Clarithromycin avium 3004166 23S rRNA 608 Mycobacterium Clarithromycin intracellulare 3004167 23S rRNA 608 Mycobacterium Azithromycin intracellulare 3003236 16S rRNA 770 Mycobacteroides Kanamycin 3003237 16S rRNA 770 Mycobacteroides Tobramycin 3003238 16S rRNA 770 Mycobacteroides Neomycin 3003239 16S rRNA 770 Mycobacteroides Amikacin 3003240 16S rRNA 770 Mycobacteroides Gentamicin 3004937 23S rRNA 838 Mycobacterium Capreomycin 3004168 23S rRNA 960 Mycobacterium Clarithromycin 3004165 23S rRNA 1278 Mycobacteroides Clarithromycin chelonae 3004169 23S rRNA 1410 Mycolicibacterium Clarithromycin 3004163 23S rRNA 1724 Mycobacteroides Clarithromycin abscessus

Example 14

Deep RNA Sequencing of Intensive Care Unit Patients with COVID-19

Purpose: COVID-19 has impacted millions of patients across the world. Molecular testing occurring now identifies the presence of the virus at the sampling site: nasopharynx, nares, or oral cavity. RNA sequencing has the potential to establish both the presence of the virus and define the host's response in COVID-19.

Methods: Single center, prospective study of patients with COVID-19 admitted to the intensive care unit where deep RNA sequencing (>100 million reads) of peripheral blood with computational biology analysis was done. All patients had positive SARS-CoV-2 PCR. Clinical data was prospectively collected.

Results: The inventors enrolled fifteen patients at a single hospital. Patients were critically ill with a mortality of 47% and 67% were on a ventilator. All the patients had the SARS-CoV-2 RNA identified in the blood in addition to RNA from other viruses, bacteria, and archaea. The expression of many immune modulating genes, including PD-L1 and PD-L2, were significantly different in patients who died from COVID-19. Some proteins were influenced by alternative transcription and splicing events, as seen in HLA-C, HLA-E. NRP1 and NRP2. Entropy calculated from alternative RNA splicing and transcription start/end predicted mortality in these patients.

Conclusions: Current upper respiratory tract testing for COVID-19 only determines if the virus is present. Deep RNA sequencing with appropriate computational biology may provide important prognostic information and point to therapeutic foci to be precisely targeted in future studies.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has led to millions of cases worldwide. Dong, Du, & Gardner, The Lancet Infectious Diseases (2020). Current testing is by polymerase chain reaction to detect viral RNA in the nares. Sethuraman, Jeremiah, & Ryo, JAMA (2020). This provides no insight into the host response. Patients with COVID-19 that require intensive care unit (ICU) care are sick and difficult to manage, thus, there is a need for other diagnostic tests during the hospital stay to assist the clinicians.

Deep RNA sequencing refers to a process of sequencing where (at least) 100 million reads of sequence are generated per sample. Deep sequencing allows for the study of low abundance RNA and biologic processes beyond gene expression. Typically. RNA sequencing data is aligned to the genome of interest, such as aligning to human genes when the sample comes from a human. Reads that do not align to the genome of interest are usually discarded. When the RNA sequencing is performed with this large number of reads, it could be used to identify the presence of specific pathogens in the blood by aligning the reads that would have been discarded to other genomes of interest. In COVID-19, sequencing reads of SARS-CoV-2 may provide insight into the biology of the virus during active illness. In addition, secondary infections could be identified, potentially allowing for better, pathogen-directed antibiotic treatment.

The host response to the virus is responsible for some of the morbidity and mortality observed. Bouadma et al., Journal of Clinical Immunology, 1-11 (2020). Acute respiratory distress syndrome (ARDS) is the most common complication encountered with COVID-19. Bouadma et al., Journal of Clinical Immunology, 1-11 (2020). The laboratory has shown that there are significant changes in alternative RNA splicing and transcription start and end in ARDS as assessed by deep RNA sequencing. Fredericks et al., Intensive Care Medicine (2020). These changes are thought to be due to the physiology of ARDS, e.g., hypoxia and acidosis, which are known to influence splicing. Whether this occurs in patients infected by COVID-19 is not known.

While RNA sequencing can be used to measure immune modulating gene expression, an alternative approach is the evaluation of global entropy, or disorder in the processing of RNA. Sterne-Weiler et al., Molecular Cell 72, 187-200.e186 (2018). The inventors found that this entropy metric combined with Principal Component Analysis (PCA) can be leveraged to distinguish COVID-19 patients that develop life-threatening illness from those likely to recover.

Here the inventors examine deep RNA sequencing data from patients in the ICU with COVID-19 to characterize both pathogens and host responses. The inventors evaluate the sequences for the presence of the SARS-CoV-2 virus and other potential infectious agents. The host response to COVID-19 is also characterized. The long-term goal is to combine these measurements to better assist clinical decision-making.

Study design, Population and Setting: The study enrolled ICU participants at a single tertiary care hospital evidence of SARS-CoV-2 infection based on positive PCR from the nasopharynx documented during admission. All participants, or their appropriate surrogate, provided informed consent as approved by the Institutional Review Board (Approval #: 411616). Blood samples were collected on day 0 of ICU admission. Clinical data including COVID specific therapies was collected prospectively from the electronic medical record and participants were followed until hospital discharge or death. Ordinal scale was collected as previously described by Beigel et al., New England Journal of Medicine (2020). See also sepsis and associated SOFA score. Singer et al., The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA, 315, 801-810 (2016). Also, with the diagnosis of ARDS. Ferguson et al., The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material. Intensive Care Medicine, 38, 1573-1582 (2012).

RNA extraction and sequencing. Whole blood was collected in PAXgene tubes (Qiagen, Germantown, Md., USA) and sent to Genewiz (South Plainfield, N.J., USA) for RNA extraction, ribosomal RNA depletion and sequencing. Sequencing was done on Illumina HiSeq machines to provide 150 base pair, paired-end reads. Libraries were prepared to have three samples per lane. Each lane provided 350 million reads ensuring each sample had >100 million reads. Raw data was returned on password protected external hard drives to ensure the security of the genomic data.

Computational Bioloqy and Statistical Analysis. All computational analysis was done blinded to the clinical data. The data was assessed for quality control using FastQC. See Andrews, A quality control tool for high throughput sequence data. FastQC. In: Editor{circumflex over ( )}Book A quality control tool for high throughput sequence data. FastQC (2014). RNA sequencing data was aligned to the human genome utilizing the STAR aligner. Dobin et al., Bioinformatics (Oxford, England) 29: 15-21 (2013). Reads that aligned to the human genome were separated and are now referred to as ‘mapped’ reads. Reads that did not align to the human genome, which are typically discarded during standard RNA sequencing analysis, were identified as ‘unmapped’ reads. The unmapped reads then aligned to the SARS-CoV-2 genome (NC_045512) and counted per sample using Magic-BLAST. Boratyn et al., BMC Bioinformatics, 20, 405 (2019). A coverage map of the SARS-CoV-2 genome was generated using al the subjects to identify the gene expression patterns of the virus in critically ill COVID-19 patients. The unmapped reads were further analyzed with Kraken2 using the PlusPFP index to identify other bacterial, fungal, archaeal, and viral pathogens. See Wood, Lu, & Langmead, Genome Biology, 20, 257 (2019).

Reads that aligned to the human genome, the mapped reads, also underwent analysis for gene expression, alternative RNA splicing, and alternative transcription start/end via Whippet. Sterne-Weiler et al., Molecular Cell 72, 187-200.e186 (2018). When comparisons were made between groups (died vs. survived) differential gene expression was set with thresholds of both p<0.05 and +/−1.5 log₂ fold change. Alternative splicing was defined as core exon, alternative acceptor splice site, alternative donor splice site, retained intron, alternative first exon and alternative last exon. Alternative transcription start/end events were defined as tandem transcription start site and tandem alternative polyadenylation site. Alternative RNA splicing and alternative transcription start/end events were also compared between groups. Sterne-Weiler et al., Molecular Cell 72, 187-200.e186 (2018). Significance was set at great than 2 log 2 fold change as previously described by Fredericks et al., Intensive Care Medicine (2020). Genes identified from the analysis of mapped reads were then evaluated by GO enrichment analysis (PANTHER Overrepresentation released 20200728). See Mi, Muruganujan, Casagrande, & Thomas. Nature Protocols. 8, 1551-1566 (2013).

Whippet was also used to generate an entropy value for every identified alternative splicing and transcription event of each gene. These entropy values are created without the need for groups used in the gene expression analysis. To visualize this data a principal component analysis (PCA) was conducted to reduce the dimensionality of the dataset and to obtain an unsupervised overview of trends in entropy values among the samples. Raw entropy values from all samples were concatenated into one matrix and missing values were replaced with column means. Mortality was then overlaid onto the PCA plot to assess the ability of these raw entropy values to predict this outcome in this sample set. This analysis was done in R (version 3.6.3).

Study Population. Participant Characteristics, and RNA sequencing: Fifteen participants were enrolled and had blood samples drawn on the first day of their ICU stay. Clinical and demographic data is reported in TABLE 1. Most participants were male (73%). There was a diverse distribution in terms of race (60% not white) and ethnicity (60% Hispanic). The most common co-morbidity was hypertension, and the median BMI was almost 30. Forty percent of participants had ARDS at the time the samples was drawn, and the patients were distributed across the top of the ordinal scale with a score of 5 as the most common in 53% of the patients. Most participants required a ventilator (67%) and 20% progressed to extracorporeal membrane oxygenation (ECMO); 27% required renal replacement. The median length of hospital stay was 22 days with a mortality rate of 47%.

All samples had sufficient RNA and RNA integrity numbers (RIN) were adequate. See Fleige & Pfaffl, Molecular Aspects of Medicine, 27, 126-139 (2006). The median of sequencing was 125,687,784 reads (95% Cl 122,164,763 to 135,800,242) and greater than 90% of those reads were more than thirty bases. After using FastQC, all samples had mean quality scores over 30. The reads mapped to the human genome 62-66% of the time.

Identification of SARS-CoV-2 and other pathogens: Among the fifteen participant samples all participants had SARS-CoV-2 RNA detected. There was a total of 676 reads that align to the SARS-CoV-2 genome with each patient having between 18 and 98 reads. See FIG. 4. Most of the reads corresponded to the RNA dependent RNA polymerase and N protein genes. RNA from other pathogens including bacteria, viruses and archaea were identified in the blood of all patients. See TABLE 2. Two participants had fungal RNA identified. Despite alignment to a robust database of organisms, each participant still had hundreds of thousands of unclassified reads. TABLE 2. The taxonomy classification of “other sequences” (28384) align to elements of cellular organisms (bacterial, archaea, plant), but do not have enough specificity to identify a single species are listed in TABLE 2. The top bacterial sequences from all patients were from either Acinetobacter baumannii or Chryseobacterium gallinarum. In patients who had the most counts of C. gallinarum, A. baumannii had significantly reduced counts compared to the counts in other patients (148.1 vs. 50905.3, p<0.05). Although sequences corresponding to A. baumannii or C. gallinarum were found in all patients, none of the patients had positive blood cultures drawn around the time of these samples. No counts of bacteria, virus, archaea, (TABLE 2) or specific bacteria correlated with mortality.

Genomic differences between participants who lived and those who died. Among participants who died there were 86 genes that increased in expression and 207 that decreased in expression (top results in TABLE 3. There were 88 significant alternative splicing events occurring in 84 unique genes (Top results TABLE 3) and 2093 alternative transcription events occurring in 1769 unique genes (Top results TABLE 3). ABCA13 was the only gene that had significant expression and alternative splicing events. Twenty-seven genes had significant expression and alternative transcription start/end differences. (TABLE 3) Eighteen genes had significantly different alternative splicing and alternative transcription start/end. (TABLE 3).

The genes that were significant between groups then underwent GO term analysis to assess significant enrichment for a biological process. The top GO terms for gene expression and alternative transcription are listed in TABLE 3. There were no significant GO terms for the genes impacted by alternative splicing.

RNA entropy as a diagnostic tool. From the over 100 million RNA sequencing reads for each participant, computational analysis via Whippet assigns an entropy value for over 380,000 RNA splicing events and alternative transcription start/end events. Principal component analysis was then applied to these >380.000 entropy scores for each of the fifteen participants and the first two principal components were plotted against each other (FIG. 5). The sample points were then labeled based on their survival status. Survival status was not part of the principal component analysis itself. Participants whose PC2 value was above 0.00 had a mortality rate of 75% (6/8), up from the total group mortality of 46% (7/15) and significantly more than the 14% for those who land below that line (1/7, p=0.04).

Discussion. This project used deep RNA sequencing of whole blood from participants in the ICU with COVID-19 as a diagnostic tool. The protocol extracted RNA from the whole blood, as opposed to fractionating the whole blood specimen. Analysis of whole blood increased the breadth of RNA being sequenced, both cell associated and cell-free, and its simplicity for clinical practice. Alternatively, more complicated techniques, such as single cell sequencing may speak more to pathogenesis but adds to the complexity of the protocol and analysis. Despite its isolation from whole blood, the RNA was of high quality. A finding using RNA from whole blood from critically ill participants is that only 62-67% of the reads mapped to the human genome. This is less than the 85-97% of reads that typically map to the reference genome. See Sequencing Quality Control Consortium. Nature Biotechnology, 32, 903-914 (2014). One major drawback is the timing needed for RNA sequencing and analysis. Sequencing machines take ˜eighteen hours to generate data. The analysis can take additional time and is not yet clinically standardized. As technology advances and speed improves, this data can be increasingly accessible in the care of ICU patients.

SARS-CoV-2 RNA was identified in the unmapped reads in all patients (FIG. 1(a)). This supports that detection of SARS-CoV-2 in the serum has been associated with clinical deterioration. Chen et al., Emerging Microbes & Infections, 9, 469-473 (2020). RT-PCR identified the SARS-CoV-2 virus in the blood more often in the ICU patients than in the non-ICU patients. Fang et al., The Journal of Infection (2020). The total number of reads in the dataset did not correlate with any outcomes, including mortality, ARDS, or coagulopathy. The low number of total reads, approximately 700 from nearly two billion from all the samples, explains the lack of success from other researchers identifying the virus in the blood. In early reports. RT-PCR directed at the N protein gene identified viral RNA in the plasma in 15% of patients. Huang et al., Lancet (London, England), 395, 497-506 (2020). The data demonstrate the two most abundant genes in blood were the RNA Dependent RNA Polymerase and the N protein (FIG. 4). With this data, the inventors identified these locations (RNA dependent RNA polymerase or N protein) as potential therapeutic or diagnostic targets. See Gordon et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

Other authors have called for robust testing for potential co-infections with SARS-CoV-2. Lai. Wang. & Hsueh, Journal of Microbiology, Immunology, and Infection, 53, 505-512 (2020). With deep sequencing and computational analysis, the inventors have identified the RNA from multiple bacteria, viruses, and archaea in all of the specimens, as well as fungal RNA in two participants. This suggests deep RNA sequencing with computational analysis may be a tool for the identification of co-infections. More data is required with comparison to gold standards such as blood culture and pathogen-specific PCR. RNA sequencing has the benefit of being able to identify all pathogens with known genomes, including both RNA and DNA based organisms. Unclassified reads that do not align to any known organism (TABLE 2) or the other sequences that have cellular organism elements (TABLE 2) could provide evidence of pathogens before a genome is sequenced or the pathogen is cultured.

Critically ill COVID-19 patients provide a difficult clinical dilemma as it pertains to antibiotics. In severely ill patients, clinicians are more likely to prescribe antibiotics despite there not being an identified pathogen. Feng et al., American Journal of Respiratory and Critical Care Medicine (2020). With identification of bacteria known to cause human disease from the RNA sequencing data, appropriate antibiotics could be prescribed to these patients. In this data set, the inventors show that there were significantly more counts of Acinetobacter baumannii in a portion of patients. This bacterium has been associated with COVID-19. Sharifipour et al., BMC Infectious Diseases, 20, 646 (2020). Using a precision medicine approach with these data, patients with significantly elevated levels may potentially be treated with directed antibiotics, in the absence of more time-consuming positive culture data. While there was no difference in survival in participants with versus without identified bacteria in this study, antibiotic use was not standardized or prescribed prospectively based upon the results. Analysis of the unmapped reads aligning to Acinetobacter baumannii (averaging over 50.000 among the six with increased reads) could provide insights into genes that are expressed in critical illness and provide useful diagnostic and therapeutic targets.

The immune response to SARS-CoV-2 has been the focus of much research since the pandemic started. Poland, Ovsyannikova, & Kennedy, Lancet (London, England) (2020). The successful use of corticosteroids in the critically ill with COVID-19 emphasizes the importance of the immune system in this disease. Dexamethasone in Hospitalized Patients with Covid-19—Preliminary Report. New England Journal of Medicine (2020); Prescott & Rice, JAMA, 324, 1292-1295 (2020). Because a significant proportion of COVID-19 patients do not respond to corticosteroids, there are still calls for a more precise approach. Waterer & Rello, Infectious Diseases and Therapy (2020). PD-1 expression is increased in certain cell populations in patients with COVID-19. Bellesi et al., British Journal of Haematology (2020). But the uses of immune checkpoint inhibitors in cancer patients have been associated with more severe COVID-19. Robilotti et al., Nature Medicine 26: 1218-1223 (2020). Other authors suggest that immune checkpoint inhibitors may be useful in COVID-19. Vivarelli et al., Cancers 12 (2020). The data shows that patients who died had increased expression of PD-L1 and PD-L2 (FIG. E1, CD274 and PDCD1Lg1, TABLE 3). This suggests that immune checkpoint inhibitors targeted against the PD-1 system might be considered in those patients identified to have increased expression of PD-L1 and PD-L2 because of their higher risk of death after ICU admission.

Numerous other immune targets are identified from these genomic changes. N4BP1 is induced by interferon and the interferon response has been implicated in COVID-19. Hadjadj et al., Science (New York, N.Y.), 369, 718-724 (2020); Lei et al., Nature Commun., 11, 3810 (2020). The data supports the role for interferons in COVID-19 as patients who died had 2.5-fold increase in expression of interferon 1 alpha (IFNA1). Clinical features of COVID-19 also correlate with some of the genes identified. OR6C4 is an olfactory gene which the inventors identified has exhibiting a 5 fold increased in expression in patients that died (TABLE 3). This finding suggests that loss of smell may signify milder disease among patients in the ICU. Thrombotic complications are common in COVID-19 patients (9.5%) and patients admitted to the ICU have a higher incidence of venous thromboembolism. Al-Samkari et al., Blood (2020). Patients who died have significant decrease in gene expression and multiple changes in alternative transcription end (TABLE 3) of both NRP1 and NRP2. Both these genes are associated with coagulation. See Rossignol, Gagnon, & Klagsbrun. Genomics 70: 211-222 (2000). The COVID-19 spike protein binds both these receptors. Daly et al., Science (New York, N.Y., 2020). Previous work has shown that there is increased expression in both genes in the lungs of patients with COVID-19 when compared to controls. See Ackermann et al., The New England Journal of Medicine, 383, 120-128 (2020). Here, the decrease NRP1 and NRP2 were seen in ICU patients who died compared to ICU patients who survived.

Many studies have attempted to utilize clinical data to predict mortality in COVID-19. See Tian et al., Journal of Medical Virology (2020);_Zhang et al., Journal of Thrombosis and Haemostasis (JTH), 18, 1324-1329 (2020). Some focus on cytokines. McElvaney et al., EBioMedicine 61, 103026 (2020). For simplicity all these attempt to identify a few variables to predict mortality. Here the inventors utilize over 380,000 variables with PCA to create a figure that improves mortality prediction based upon where the patient is on the graph (FIG. 5, 75% versus 14%). A limitation to this form of analysis is that the PCA cannot identify a specific gene or event most responsible for outcomes; it uses all 380.000 data points. Accurate assessment of prognosis using sequencing technology might be valuable to inform end of life care discussions in the ICU.

Despite the limitations of this single-center study with a small patient number, the inventors were still able to document that deep RNA sequencing and appropriate computational analysis yields valuable insight into the pathogenesis and host response of COVID-19 in critically ill patients. Useful drug targets were identified from SARS-CoV-2 RNA and the host response, including RNA dependent RNA polymerase, the N protein, and the PD-1 immune checkpoint pathway. The presence of pathogen RNA in the blood suggests co-infection should be reconsidered. Most importantly, PCA of the entropy of >380,000 events allowed use to group patients into those likely to die versus those likely to live, and this may be helpful in family discussions with critically ill patients. Translating these results to clinical practice can improve the diagnosis, assessment of prognosis, and therapy of COVID-19.

Example 15 Alternative RNA Splicing and Alternative Transcription Start/End in Acute Respiratory Distress Syndrome

Critically ill patients develop acute respiratory distress syndrome (ARDS) and despite the study of genomics of ARDS, there is little progress. The drop in the cost of sequencing has refocused genetic studies from DNA to RNA sequencing and methods to analyze this data have improved. The objective of this investigation is to utilize RNA sequencing data and analysis to identify useful gene targets in ARDS.

The human cohort generated from the GTEx consortium consisted of 25 deceased patients with ARDS identified by the presence of diffuse alveolar damage (DAD), and 74 deceased patients evaluated to not have DAD. The mouse ARDS cohort included C57BL/6 mice ages 10-12 in a model previously described and compared to controls.

Alternatively spliced RNA arises from co/post-transcriptional events facilitated by the spliceosome, introns are removed to form the mature RNA from which protein isoforms are translated. Alternatively transcribed genes are the product of changes in promoter usage, polyadenylation signals, and RNA polymerase II interactions with DNA which can lead to changes in isoform usage like alternative splicing events. These are identified from the analysis of RNA sequencing data. Significant differentially alternatively transcribed genes and alternative spliced genes were identified and where alternative transcription may have separate roles in DAD/ARDS by regulating different genes to perform distinctive functions.

In this analysis of RNA sequencing data from deceased patients with ARDS identified by the presence of DAD and a clinically relevant mouse model of ARDS, useful genes were identified. Future research is needed using on the mechanism of alternative RNA splicing and alternative transcription start/end seen in ARDS, overlapped with genes previously reported as ARDS related. Of 89 reported ARDS related genes, 38 were confirmed in at least one differential category confirming that the use of humans and mice with DAD/ARDS is appropriate and robust (p=1.25e−14). Eleven previously reported genes were present in all categories. These eleven genes were evaluated for the change in alternative splicing and alternative transcription. GO term enrichment analysis was performed on the 11 overlapping genes, revealing 20 significant biological processes including ontology related to aging, and response to abiotic/environmental stimuli. There are 1639 genes that show overlap in alternative splicing and alternative transcription that were not previously in the literature. These genes were assessed for directionality alternative splicing and alternative transcription and GO terms should provide the foundation for future work in ARDS.

Studying the underlying changes in RNA processing (alternative splicing and alternative transcription start/end) not only expands basic knowledge of pathogenicity, but also provides additional targets for therapeutics. The most enriched GO term from the alternative splicing set, carboxy-terminal domain protein kinase complex (GO: 0032806) refers to phosphorylation of the CTD of RNA polymerase II, which is vital in the regulation of transcription and RNA processing. In addition, RNA polymerase complex binding (GO: 0000993), and transport of the SLBP Independent/Dependent mature mRNA (R-HSA-159227; R-HSA-159230) are among the most enriched. This suggests alternative pre-mRNA splicing plays the dominate role in isoform usage in genes where expressions levels do not change, whereas alternative transcription may regulate isoform usage in genes that are more dynamically expressed during critical illness. Although it is possible the enrichment reflects down regulation through inhibitory genes, these data support the hypothesis that alternative splicing. Although it is possible the enrichment reflects down regulation through inhibitory genes, these data support the hypothesis that alternative splicing and alternative transcription may have separate roles in DAD/ARDS by regulating different genes to perform distinctive functions.

In this analysis of RNA sequencing data from deceased patients with ARDS identified by the presence of DAD and a clinically relevant mouse model of ARDS, useful genes were identified. Future research is needed using on the mechanism of alternative RNA splicing and alternative transcription start/end seen in ARDS.

Example 16 Updated Results

To translate the work described above, where SARS-CoV-2 was identified in the blood of patients using this methodology, the inventors again showed that they do this for other infections, specifically the bacterial infection Escherichia coli.

In a patient with a known Escherichia coli infection the blood of that patient was sequenced to a depth of >100 million reads. Sequencing data was aligned using STAR aligner with standard parameters to the human genome. Unmapped reads were extracted and then aligned to the Escherichia coli genome (Escherichia coli O25b:H4-ST131).

The reads aligned to Escherichia coli in a patients with an Escherichia coli infection. See TABLE 7.

TABLE 7 All E. coli reads Start End Nucleic Acid Sequence 242185 242285 TGACTCTTGAAATCCATAAATTCAAGCGCAGTGCCCAGCCAT CCCGATACTGCTGCTTTCACCAAATCCTTAGTGCTTCTTTCGT GTTTTTCTATTGTCATAATGTTATCTCTAAAAAAGAGGTAAGAT GCGTACTACTTACTCGCCGTT 242285 242185 TGTTATCTCTAAAAAAGAGGTAAGATGCGTACTACTTACTCGC CGTTATTGGTATTATTCAGAAAAAGTGAGTAAGACTTTGCAGC AATGTTTTTGATCCTGTTCAAATAAACTAATGGCATCAGCAAC ATGCTGGAAATCAAACGTATG 1500318 1500404 CGGCCTATCAACGTCGTCGTCTTCAACGTTCCTTCAGGACTC TCAAGGAGTCAGGGAGAACTCATCTCGGGGCAAGTTTCGTG CTTAGATGCTTTCAGCACTTATCTCTTCCGCATTTAGCTACCG GGCAGTGCCATTGGCATGACAACC 1500404 1500318 AGATGCTTTCAGCACTTATCTCTTCCGCATTTAGCTACCGGG CAGTGCCATTGGCATGACAACCCGAACACCAGTGATGCGTC CACTCCGGTCCTCTCGTACTAGGAGCAGCCCCCCTCAGTTCT CCAGCGCCCACGGCAGATAGGGACC 1 501520 1501548 CTTGGTATTCTCTACCTGACCACCTGTGTCGGTTTGGGGTAC GATTTGATGTTACCTGATGCTTAGAGGCTTTTCCTGGAAGCA GGGCATTTGTCGCTTCAGCACCGTAGTGCCTCGTCATCACGC CTCAGCCTTGATTTTCCGGATTTG 1501548 1501520 TCGGTTTGGGGTACGATTTGATGTTACCTGATGCTTAGAGGC TTTTCCTGGAAGCAGGGCATTTGTCGCTTCAGCACCGTAGTG CCTCGTCATCACGCCTCAGCCTTGATTTTCCGGATTTGCCTG GAAAACCAGCCTACACGCTTAAAC 1501563 1501563 ATTTGATGTTACCTGATGCTTAGAGGCTTTTCCTGGAAGCAG GGCATTTGTCGCTTCAGCACCGTAGTGCCTCGTCATCACGC CTCAGCCTTGATTTTCCGGATTTGCCTGGAAAACCAGCCTAC ACGCTTAAACAGATCGGAAGAGCGT 1501563 1501563 GTGCTCTTCCGATCTATTTGATGTTACCTGATGCTTAGAGGC TTTTCCTGGAAGCAGGGCATTTGTCGCTTCAGCACCGTAGTG CCTCGTCATCACGCCTCAGCCTTGATTTTCCGGATTTGCCTG GAAAACCAGCCTACACGCTTAAAC 1501821 1501900 CACCCTGCCCCGATTAACGTTGGACAGGAACCCTTGGTCTTC CGGCGAGCGGGCTTTTCACCCGCTTTATCGTTACTTATGTCA GCATTCGCACTTCTGATACCTCCAGCATACCTCACAGTACAC GTTCACAGGCTTACAGAACGCTGC 1501900 1501821 TGTCAGCATTCGCACTTCTGATACCTCCAGCATACCTCACAG TACACCTTCACAGGCTTACAGAACGCTCCCCTACCCAACAAC ACATAGTGTCGCTGCCGCAGCTTCGGTGCATGGTTTAGCCC CGTTACATCTTCCGCGCAGGCCGAC 1502166 1502187 GGCGGTCTGGGTTGTTTCCCTCTTCACGACGGACGTTAGCA CCCGCCGTGTGTCTCCCGTGATAACATTCTCCGGTATTCGCA GTTTGCATCGGGTTGGTAAGTCGGGATGACCCCCTTGCCGA AACAGTGCTCTACCCCCGGAGATGAA 1502166 2227814 GGCGGTCTGGGTTGTTTCCCTCTTCACGACGGACGTTAGCA CCCGCCGTGTGTCTCCCGTGATAACATTCTCCGGTATTCGCA GTTTGCATCGGGTTGGTAAGTCGGGATGACCCCCTTGCCGA AACAGATCGGAAGAGCACACGTCTGA 1502166 2018481 GGCGGTCTGGGTTGTTTCCCTCTTCACGACGGACGTTAGCA CCCGCCGTGTGTCTCCCGTGATAACATTCTCCGGTATTCGCA GTTTGCATCGGGTTGGTAAGTCGGGATGACCCCCTTGCCGA AACAGATCGGAAGAGCACACGTCTGA 1502176 2317776 GTTGTTTCCCTCTTCACGACGGACGTTAGCACCCGCCGTGT GTCTCCCGTGATAACATTCTCCGGTATTCGCAGTTTGCATCG GGTTGGTAAGTCGGGATGACCCCCTTGCCGAAACAGTGCTC TACCCCCGGAGATGAATTCACGAGAT 1502187 1502166 CTTCACGACGGACGTTAGCACCCGCCGTGTGTCTCCCGTGA TAACATTCTCCGGTATTCGCAGTTTGCATCGGGTTGGTAAGT CGGGATGACCCCCTTGCCGAAACAGTGCTCTACCCCCGGAG ATGAATTCACGAGGCGCTACCTAAAT 1502487 1502523 CGGGTCTATACCCTGCAACTTAACGCCCAGTTAAGACTCGGT TTCCCTTCGGCTCCCCTATTCGGTTAACCTTGCTACAGAATAT AAGTCGCTGACCCATTATACAAAAGGTACGCAGTCACCCCAT TAAGAGGCTCCCACTGCTTGTAC 1502523 1502487 CTCGGTTTCCCTTCGGCTCCCCTATTCGGTTAACCTTGCTAC AGAATATAAGTCGCTGACCCATTATACAAAAGGTACGCAGTC ACCCCATTAAGAGGCTCCCACTGCTTGTACGTACACGGTTTC AGGTTCTTTTTCACTCCCCTCGCC 1502812 1502812 TTTTTGTGTACGGGGCTGTCACCCTGTATCGCGCGCCTTTCC AGACGCTTCCACTAACACACACACTGATTCAGGCTCTGGGCT CCTCCCCGTTCGCTCGCCGCTACTGGGGGAATCTCGGTTGA TTTCTTAGATCGGAAGAGCACACGT 1502812 1502812 CACGACGCTCTTCCGATCTTTTTTGTGTACGGGC5CTGTCACC CTGTATCGCGCGCCTTTCCAGACGCTTCCACTAACACACACA CTGATTCAGGCTCTGGGCTCCTCCCCGTTCGCTCGCCGCTA CTGGGGGAATCTCGGTTGATTTCTT 1502923 1502923 GGAATCTCGGTTGATTTCTTTTCCTCGGGGTACTTAGATGTTT CAGTTCCCCCGGTTCGCCTCATTAACCTATGGATTCAGTTAA TGATAGTGTGTCGAAACACACTGGGTTTCCCCATTCGGAAAT CGCCGAGATCGGAAGAGCACACG 1502923 1502923 ACGACGCTCTTCCGATCTGGAATCTCGGTTGATTTCTTTTCCT CGGGGTACTTAGATGTTTCAGTTCCCCCGGTTCGCCTCATTA ACCTATGGATTCAGTTAATGATAGTGTGTCGAAACACACTGG GTTTCCCCATTCGGAAATCGCCG 1503664 1503684 CAAGGCCCGGGAACGTATTCACCGTGGCATTCTGATCCACG ATTACTAGCGATTCCGACTTCATGGAGTCGAGTTGCAGACTC CAATCCGGACTACGACGCACTTTATGAGGTCCGCTTGCTCTC GCAGATCGGAAGAGCACACGTCTGA 1503664 1503664 CCTACACGACGCTCTTCCGATCTCAAGGCCCGGGAACGTAT TCACCGTGGCATTCTGATCCACGATTACTAGCGATTCCGACT TCATGGAGTCGAGTTGCAGACTCCAATCCGGACTACGACGC ACTTTATGAGGTCCGCTTGCTCTCGC 1503671 CGGGA GGGGAACGTATTCACCGTGGCATTCTGATCCACGATTACTAG ACG CGATTCCGACTTCATGGAGTCGAGTTGCAGACTCCAATCCG GACTACGACGCACTTTATGAGGTCCGCTTGCTCTCGCAGATC GGAAGAGCGTCGTGTAGGGAAAGAG 1503812 1503849 CGCCATTGTAGCACGTGTGTAGCCCTGGTCGTAAGGGCCAT GATGACTTGACGTCATCCCCACCTTCCTCCAGTTTATCACTG GCAGTCTCCTTTGAGTTCCCGGCCGGACCGCTGGCAACAAA GGATAAGGGTTGCGCTCGTTGCGGGA 1503849 1503812 CCATGATGACTTGACGTCATCCCCACCTTCCTCCAGTTTATC ACTGGCAGTCTCCTTTGAGTTCCCGGCCGGACCGCTGGCAA CAAAGGATAAGGGTTGCGCTCGTTGCGGGACTTAACCCAAC ATTTCACAACACGAGCTGACGACAGC 1503942 1503953 CGGGTTGCGCTCGTTGCGGGACTTAACCCAACATTTCACAAC ACGAGCTGACGACAGCCATGCAGCACCTGTCTCACGGTTCC CGAAGGCACATTCTCATCTCTGAAAACTTCCGTGGATGTCAA GACCAGGTAAGGTTCTTCGCGTTGC 1503953 1503942 GTTGCGGGACTTAACCCAACATTTCACAACACGAGCTGACGA CAGCCATGCAGCACCTGTCTCACGGTTCCCGAAGGCACATT CTCATCTCTGAAAACTTCCGTGGATGTCAAGACCAGGTAAGG TTCTTCGCGTTGCATCGAATTAAAC 1504092 1504092 TTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGCCCCC GTCAATTCATTTGAGTTTTAACCTTGCGGCCGTACTCCCCAG GCGGTCAACTTAATGCGTTAGCTGCGCCACTAAAAGCTCAAG GCTTCCAACAGATCGGAAGAGCACA 1504092 1504092 GACGCTCTTCCGATCTTTCGAATTAAACCACATGCTCCACCG CTTGTGCGGGCCCCCGTCAATTCATTTGAGTTTTAACCTTGC GGCCGTACTCCCCAGGCGGTCAACTTAATGCGTTAGCTGCG CCACTAAAAGCTCAAGGCTTCCAAC 1504400 1504439 CTCAAGCTTGCCAGTATCAGATGCAGTTCCCAGGTTGAGCCC GGGGATTTCACATCTGACTTAACAAACCGCCTGCGTGCGCTT TACGCCCAGTAATTCCGATTAACGCTTGCACCCTCCGTATTA CCGCGGCTGCTGGCACGGAGTTAG 1504439 1504400 CCCGGGGATTTCACATCTGACTTAACAAACCGCCTGCGTGC GCTTTACGCCCAGTAATTCCGATTAACGCTTGCACCCTCCGT ATTACCGCGGCTGCTGGCACGGAGTTAGCCGGTGCTTCTTC TGCGGGTAACGTCAATGAGCAAAGGT 2018481 1502166 CCTACACGACGCTCTTCCGATCTGGCGGTCTGGGTTGTTTCC CTCTTCACGACGGACGTTAGCACCCGCCGTGTGTCTCCCGT GATAACATTCTCCGGTATTCGCAGTTTGCATCGGGTTGGTAA GTCGGGATGACCCCCTTGCCGAAAC 2227814 1502166 CCTACACGACGCTCTTCCGATCTGGCGGTCTGGGTTGTTTCC CTCTTCACGACGGACGTTAGCACCCGCCGTGTGTCTCCCGT GATAACATTCTCCGGTATTCGCAGTTTGCATCGGGTTGGTAA GTCGGGATGACCCCCTTGCCGAAAC 2260692 2260927 GTCACGCTCAAAGACGCGGGTCATATAGCCTTTCAGCTCTTT CGCACCCGGGCCGCTGAACTCGATGCCCAGTTGCGGCAGA CGCCACAGCAGCGGAGCAAGATAGCAATCGACCAGGCTGAA CTCATCGCTCAGGAAGTACGGCTTCTG 2260927 2260692 GTGTTCATCAGCGTGTACCAGTCTTTTTCGATGGGATGCATG TACAGACGGCTTTCACCGCGAGCTACCGGGTAAACAGGCAT CAGTGGCGGATGCGGGAAACGCTCATCCAGATAGTCCATAA TGATGCGAGATTCCCACAGGGTCAGC 2315078 2315109 GTTGTTTGATGAGCCAACGTCGGCGCTCGATCCTGAGATGG TGAAAGAGGTGCTGGATACGATGATTGGGCTGGCGCAGTCG GGTATGACAATGCTGTGTGTAACACATGAGATGGGGTTTGCA CGAACCGTCGCTGACCGGGTGATTTT 2315109 2315078 CCTGAGATGGTGAAAGAGGTGCTGGATACGATGATTGGGCT GGCGCAGTCGGGTATGACAATGCTGTGTGTAACACATGAGA TGGGGTTTGCACGAACCGTCGCTGACCGGGTGATTTTTATG GATCGTGGGGAGATAGTGGAACAAGCT 2315918 2316004 CGGCCTATCAACGTCGTCGTCTTCAACGTTCCTTCAGGACTC TCAAGGAGTCAGGGAGAACTCATCTCGGGGCAAGTTTCGTG CTTAGATGCTTTCAGCACTTATCTCTTCCGCATTTAGCTACCG GGCAGTGCCATTGGCATGACAACC 2316004 2315918 AGATGCTTTCAGCACTTATCTCTTCCGCATTTAGCTACCGGG CAGTGCCATTGGCATGACAACCCGAACACCAGTGATGCGTC CACTCCGGTCCTCTCGTACTAGGAGCAGCCCCCCTCAGTTC TCCAGCGCCCACGGCAGATAGGGACC 2317120 2317148 CTTGGTATTCTCTACCTGACCACCTGTGTCGGTTTGGGGTAC GATTTGATGTTACCTGATGCTTAGAGGCTTTTCCTGGAAGCA GGGCATTTGTCGCTTCAGCACCGTAGTGCCTCGTCATCACG CCTCAGCCTTGATTTTCCGGATTTG 2317148 2317120 TCGGTTTGGGGTACGATTTGATGTTACCTGATGCTTAGAGGC TTTTCCTGGAAGCAGGGCATTTGTCGCTTCAGCACCGTAGTG CCTCGTCATCACGCCTCAGCCTTGATTTTCCGGATTTGCCTG GAAAACCAGCCTACACGCTTAAAC 2317163 2317163 ATTTGATGTTACCTGATGCTTAGAGGCTTTTCCTGGAAGCAG GGCATTTGTCGCTTCAGCACCGTAGTGCCTCGTCATCACGC CTCAGCCTTGATTTTCCGGATTTGCCTGGAAAACCAGCCTAC ACGCTTAAACAGATCGGAAGAGCGT 2317163 2317163 GTGCTCTTCCGATCTATTTGATGTTACCTGATGCTTAGAGGC TTTTCCTGGAAGCAGGGCATTTGTCGCTTCAGCACCGTAGTG CCTCGTCATCACGCCTCAGCCTTGATTTTCCGGATTTGCCTG GAAAACCAGCCTACACGCTTAAAC 2317766 2317787 GGCGGTCTGGGTTGTTTCCCTCTTCACGACGGACGTTAGCA CCCGCCGTGTGTCTCCCGTGATAACATTCTCCGGTATTCGCA GTTTGCATCGGGTTGGTAAGTCGGGATGACCCCCTTGCCGA AACAGTGCTCTACCCCCGGAGATGAA 2317776 1502176 ATCTGTTGTTTCCCTCTTCACGACGGACGTTAGCACCCGCCG TGTGTCTCCCGTGATAACATTCTCCGGTATTCGCAGTTTGCA TCGGGTTGGTAAGTCGGGATGACCCCCTTGCCGAAACAGTG CTCTACCCCCGGAGATGAATTCACG 2317787 2317766 CTTCACGACGGACGTTAGCACCCGCCGTGTGTCTCCCGTGA TAACATTCTCCGGTATTCGCAGTTTGCATCGGGTTGGTAAGT CGGGATGACCCCCTTGCCGAAACAGTGCTCTACCCCCGGAG ATGAATTCACGAGGCGCTACCTAAAT 2318087 2318123 CGGGTCTATACCCTGCAACTTAACGCCCAGTTAAGACTCGGT TTCCCTTCGGCTCCCCTATTCGGTTAACCTTGCTACAGAATAT AAGTCGCTGACCCATTATACAAAAGGTACGCAGTCACCCCAT TAAGAGGCTCCCACTGCTTGTAC 2318123 2318087 GTCGGTTTCCCTTCGGCTCCCCTATTCGGTTAACCTTGCTAC AGAATATAAGTCGCTGACCCATTATACAAAAGGTACGCAGTC ACCCCATTAAGAGGCTCCCACTGCTTGTACGTACACGGTTTC AGGTTCTTTTTCACTCCCCTCGCC 2318412 2318412 TTTTTGTGTACGGGGCTGTCACCCTGTATCGCGCGCCTTTCC AGACGCTTCCACTAACACACACACTGATTCAGGCTCTGGGCT CCTCCCCGTTCGCTCGCCGCTACTGGGGGAATCTCGGTTGA TTTCTTAGATCGGAAGAGCACACGT 2318412 2318412 CACGACGCTCTTCCGATCTTTTTTGTGTACGGGGCTGTCACC CTGTATCGCGCGCCTTTCCAGACGCTTCCACTAACACACACA CTGATTCAGGCTCTGGGCTCCTCCCCGTTCGCTCGCCGCTA CTGGGGGAATCTCGGTTGATTTCTT 2318523 2318523 GGAATCTCGGTTGATTTCTTTTCCTCGGGGTACTTAGATGTTT CAGTTCCCCCGGTTCGCCTCATTAACCTATGGATTCAGTTAA TGATAGTGTGTCGAAACACACTGGGTTTCCCCATTCGGAAAT CGCCGAGATCGGAAGAGCACACG 2318523 2318523 ACGACGCTCTTCCGATCTGGAATCTCGGTTGATTTCTTTTCCT CGGGGTACTTAGATGTTTCAGTTCCCCCGGTTCGCCTCATTA ACCTATGGATTCAGTTAATGATAGTGTGTCGAAACACACTGG GTTTCCCCATTCGGAAATCGCCG 2319355 2319355 CAAGGCCCGGGAACGTATTCACCGTGGCATTCTGATCCACG ATTACTAGCGATTCCGACTTCATGGAGTCGAGTTGCAGACTC CAATCCGGACTACGACGCACTTTATGAGGTCCGCTTGCTCTC GCAGATCGGAAGAGCACACGTCTGA 2319355 2319355 CCTACACGACGCTCTTCCGATCTCAAGGCCCGGGAACGTAT TCACCGTGGCATTCTGATCCACGATTACTAGCGATTCCGACT TCATGGAGTCGAGTTGCAGACTCCAATCCGGACTACGACGC ACTTTATGAGGTCCGCTTGCTCTCGC 2319362 1503671 CTGGAGTTCAGACGTGTGCTCTTCCGATCTCGGGAACGTATT CACCGTGGCATTCTGATCCACGATTACTAGCGATTCCGACTT CATGGAGTCGAGTTGCAGACTCCAATCCGGACTACGACGCA CTTTATGAGGTCCGCTTGCTCTCGC 2319503 2319540 CGCCATTGTAGCACGTGTGTAGCCCTGGTCGTAAGGGCCAT GATGACTTGACGTCATCCCCACCTTCCTCCAGTTTATCACTG GCAGTCTCCTTTGAGTTCCCGGCCGGACCGCTGGCAACAAA GGATAAGGGTTGCGCTCGTTGCGGGA 2319540 2319503 CCATGATGACTTGACGTCATCCCCACCTTCCTCCAGTTTATC ACTGGCAGTCTCCTTTGAGTTCCCGGCCGGACCGCTGGCAA CAAAGGATAAGGGTTGCGCTCGTTGCGGGACTTAACCCAAC ATTTCACAACACGAGCTGACGACAGC 2319633 2319644 CGGGTTGCGCTCGTTGCGGGACTTAACCCAACATTTCACAAC ACGAGCTGACGACAGCCATGCAGCACCTGTCTCACGGTTCC CGAAGGCACATTCTCATCTCTGAAAACTTCCGTGGATGTCAA GACCAGGTAAGGTTCTTCGCGTTGC 2319644 2319633 GTTGCGGGACTTAACCCAACATTTCACAACACGAGCTGACGA CAGCCATGCAGCACCTGTGTCACGGTTCCCGAAGGCACATT CTCATCTCTGAAAACTTCCGTGGATGTCAAGACCAGGTAAGG TTCTTCGCGTTGCATCGAATTAAAC 2319783 2319783 TTCGAATTAAACCACATGCTCCACCGCTTGTGCGGGCCCCC GTCAATTCATTTGAGTTTTAACCTTGCGGCCGTACTCCCCAG GCGGTCAACTTAATGCGTTAGCTGCGCCACTAAAAGCTCAAG GCTTCCAACAGATCGGAAGAGCACA 2319783 2319783 GACGCTCTTCCGATCTTTCGAATTAAACCACATGCTCCACCG CTTGTGCGGGCCCCCGTCAATTCATTTGAGTTTTAACCTTGC GGCCGTACTCCCCAGGCGGTCAACTTAATGCGTTAGCTGCG GCACTAAAAGCTCAAGGCTTCCAAC 2320091 2320130 CTCAAGCtfGCCAGTATCAGATGCAGTTCCCAGGTTGAGCCC GGGGATTTCACATCTGACTTAACAAACCGCCTGCGTGCGCTT TACGCCCAGTAATTCCGATTAACGCTTGCACCCTCCGTATTA CCGCGGCTGCTGGCACGGAGTTAG 2320130 2320091 CCCGGGGATTTCACATCTGACTTAACAAACCGCCTGCGTGC GCTTTACGCGCAGTAATTCCGATTAACGCTTGCACCCTCCGT ATTACCGCGGCTGCTGGCACGGAGTTAGCCGGTGCTTCTTC TGCGGGTAACGTCAATGAGCAAAGGT 2320361 2320375 GGCTTGCGCCCATTGTGCAATATTCCCCACTGCTGCCTCCC GTAGGAGTCTGGACCGTGTCTCAGTTCCAGTGTGGCTGGTC ATCCTCTCAGACCAGCTAGGGATCGTCGCCTAGGTGAGCCA TTACCCCACCTACTAGCTAATCCCATC 2320375 2320361 GTGCAATATTCCCCACTGCTGCCTCCCGTAGGAGTCTGGAC CGTGTCTCAGTTCCAGTGTGGCTGGTCATCCTCTCAGACCAG CTAGGGATCGTCGCCTAGGTGAGCCATTACCCCACCTACTA GCTAATCCCATCTGGGCACATCCGAT 2345096 2345096 CGGGGAGATCAGAACAGTGAAGCGCTCTTTGCGTGTCGGCA GCGGGATCGGACCACGGACCTGCGCACCAGTGCGCTTAGA AGTCTCGACGATTTCCGCGGTTGCTTGATCGATCAGACGATG ATCAAACGCTTTAGATCGGAAGAGCAC 2345096 2345096 ACGCTCTTCCGATCTCGGGGAGATCAGAACAGTGAAGCGCT CTTTGCGTGTCGGCAGCGGGATCGGACCACGGACCTGCGC ACCAGTGCGCTTAGCAGTCTCGACGATTTCCGCGGTTGCTT GATCGATCAGACGATGATCAAACGCTTT 2833276 2833282 CCCAGATGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCT AGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCAC ACTGGAACTGAGACACGGTCCAGACTCCTACGGGAGGCAGC AGTGGGGAATATTGCACAATGGGCGCA 2833282 2833276 TGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCTAGGCGA CGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGA ACTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGG GGAATATTGCACAATGGGCGCAAGCCTG 2833511 2833550 ACCTTTGCTCATTGACGTTACCCGCAGAAGAAGCACCGGCTA ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAAGC GTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGGTT TGTTAAGTCAGATGTGAAATCCCCGGG 2833550 2833511 CTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAA GCGTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGG TTTGTTAAGTCAGATGTGAAATCCCCGGGCTCAACCTGGGAA CTGCATCTGATACTGGCAAGCTTGAG 2833900 2833900 GTTGGAAGCCTTGAGCTTTTAGTGGCGCAGCTAACGCATTAA GTTGACCGCCTGGGGAGTACGGCCGCAAGGTTAAAACTCAA ATGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGT TTAATTCGAAAGATCGGAAGAGCGTC 2833900 2833900 TGTGCTCTTCCGATCTGTTGGAAGCCTTGAGCTTTTAGTGGC GCAGCTAACGCATTAAGTTGACCGCCTGGGGAGTACGGCCG CAAGGTTAAAACTCAAATGAATTGACGGGGGCCCGCACAAG CGGTGGAGCATGTGGTTTAATTCGAA 2833997 2834009 GTTTAATTCGATGCAACGCGAAGAACCTTACCTGGTCTTGAC ATCCACGGAAGTTTTCAGAGATGAGAATGTGCCTTCGGGAAC CGTGAGACAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGT GAAATGTTGGGTTAAGTCCCGCAAC 2834009 2833997 GCAACGCGAAGAACCTTACCTGGTCTTGACATCCACGGAAG TTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACAG GTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGG GTTAAGTCCCGCAACGAGCGCAACCCG 2834049 2948544 GTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAACGAGCGCAAGATCGGAAGAGCACACG TCTGAACTCCAGTCACAACCTACGATC 2834049 3077599 GTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAACGAGCGCAAGATCGGAAGAGCACACG TCTGAACTCCAGTCACAACCTACGATC 2834049 3117867 GTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAACGAGCGCAAGATCGGAAGAGCACACG TCTGAACTCCAGTCACAACCTACGATC 2834101 2834138 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCG CAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAG GTGGGGATGACGTCAAGTCATCATGG 2834138 2834101 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGT CCGGCCGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGA GGAAGGTGGGGATGACGTCAAGTCATCATGGCCCTTACGAC CAGGGCTACACACGTGCTACAATGGCG 2834151 2948646 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACT CAAAGGAGAGTGCCAGTGATAAACTGGAGGAAGGTGGGGAT GACGTCAAGTCATCATGGCCCTTACGACCAGGGCTACACAC GTGCTACAATGGCGCATACAAAGAGAT 2834151 3077701 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACT CAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGGGGAT GACGTCAAGTCATCATGGCCCTTACGACCAGGGCTACACAC GTGCTACAATGGCGCATACAAAGAGAT 2834151 3117969 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACT CAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGGGGAT GACGTCAAGTCATCATGGCCCTTACGACCAGGGCTACACAC GTGCTACAATGGCGCATACAAAGAGAT 2834309 2834309 GCGAGAGCAAGCGGACCTCATAAAGTGCGTCGTAGTCCGGA TTGGAGTCTGCAACTCGACTCCATGAAGTCGGAATCGCTAGT AATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCC TTGAGATCGGAAGAGCGTCGTGTAGG 2834309 2834309 TCAGACGTGTGCTCTTCCGATCTGCGAGAGCAAGCGGACCT CATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGA CTCCATGAAGTCGGAATCGCTAGTAATCGTGGATCAGAATGC CACGGTGAATACGTTCCCGGGCCTTG 2835045 2835045 CGGCGATTTCCGAATGGGGAAACCCAGTGTGTTTCGACACA CTATCATTAACTGAATCCATAGGTTAATGAGGCGAACCGGGG GAACTGAAACATCTAAGTACCCCGAGGAAAAGAAATCAACCG AGATTCCAGATCGGAAGAGCGTCGT 2835045 2835045 CGTGTGCTCTTCCGATCTCGGCGATTTCCGAATGGGGAAAC CCAGTGTGTTTCGACACACTATCATTAACTGAATCCATAGGTT AATGAGGCGAACCGGGGGAACTGAAACATCTAAGTACCCCG AGGAAAAGAAATCAACCGAGATTCC 2835157 2835157 AAGAAATCAACCGAGATTCCCCCAGTAGCGGCGAGCGAACG GGGAGGAGCCCAGAGCCTGAATCAGTGTGTGTGTTAGTGGA AGCGTCTGGAAAGGCGCGCGATACAGGGTGACAGCCCCGT ACACAAAAAAGATCGGAAGAGCGTCGTG 2835157 2835157 ACGTGTGCTCTTCCGATCTAAGAAATCAACCGAGATTCCCCC AGTAGCGGCGAGCGAACGGGGAGGAGCCCAGAGCCTGAAT CAGTGTGTGTGTTAGTGGAAGCGTCTGGAAAGGCGCGCGAT ACAGGGTGACAGCCCCGTACACAAAAA 2835427 2835463 GGCGAGGGGAGTGAAAAAGAACCTGAAACCGTGTACGTACA AGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACCTTTTGT ATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTAACCGA ATAGGGGAGCCGAAGGGAAACCGAG 2835463 2835427 GTACAAGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACC TTTTGTATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTA ACCGAATAGGGGAGCCGAAGGGAAACCGAGTCTTAACTGGG CGTTAAGTTGCAGGGTATAGACCCG 2835763 2835784 ATTTAGGTAGCGCCTCGTGAATTCATCTCCGGGGGTAGAGC ACTGTTTCGGCAAGGGGGTCATCCCGACTTACCAACCCGAT GCAAACTGCGAATACCGGAGAATGTTATCACGGGAGACACA CGGCGGGTGCTAACGTCCGTCGTGAAG 2835778 2950271 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACAGAT 2835778 3079417 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACAGAT 2835778 3119594 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACAGAT 2835778 2950271 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACCCAG 2835778 3079417 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACCCAG 2835778 3119594 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACCCAG 2835784 2835763 TTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGGGGGTCA TCCCGACTTACCAACCCGATGCAAACTGCGAATACCGGAGA ATGTTATCACGGGAGACACACGGCGGGTGCTAACGTCCGTC GTGAAGAGGGAAACAACCCAGACCGCC 2836402 2836402 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATAGATCGGAAGAGCAC 2836402 2836402 ACGCTCTTCCGATCTGTTTAAGCGTGTAGGCTGGTTTTCCAG GCAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCA CTACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAG CCTCTAAGCATCAGGTAACATCAAAT 2836402 2836430 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATCGTACCCCAAACCGA 2836430 2836402 CAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCAC TACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAGC CTCTAAGCATCAGGTAACATCAAATCGTACCCCAAACCGACA CAGGTGGTCAGGTAGAGAATACCAAG 2837546 2837632 GGTCCCTATCTGCCGTGGGCGCTGGAGAACTGAGGGGGGC TGCTCCTAGTACGAGAGGACCGGAGTGGACGCATCACTGGT GTTCGGGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAAT GCGGAAGAGATAAGTGCTGAAAGCATCT 2837632 2837546 GGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAATGCGGA AGAGATAAGTGCTGAAAGCATCTAAGCACGAAACTTGCCCCG AGATGAGTTCTCCCTGACTCCTTGAGAGTCCTGAAGGAACGT TGAAGACGACGACGTTGATAGGCCG 2947561 2947567 CTCAGATTGAACGCTGGCGGCAGGCCTAACACATGCAAGTC GAACGGTAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTG GCGGACGGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGG GGGATAACTACTGGAAACGGTAGCTAA 2947567 2947561 TTGAACGCTGGCGGCAGGCCTAACACATGCAAGTCGAACGG TAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTGGCGGAC GGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGGGGGATA ACTACTGGAAACGGTAGCTAATACCGC 2947771 2947777 CCCAGATGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCT AGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCAC ACTGGAACTGAGACACGGTCCAGACTCCTACGGGAGGCAGC AGTGGGGAATATTGCACAATGGGCGCA 2947777 2947771 TGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCTAGGCGA CGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGA ACTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGG GGAATATTGCACAATGGGCGCAAGCCTG 2948006 2948045 ACCTTTGCTCATTGACGTTACCCGCAGAAGAAGCACCGGCTA ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAAGC GTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGGTT TGTTAAGTCAGATGTGAAATCCCCGGG 2948045 2948006 CTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAA GCGTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGG TTTGTTAAGTCAGATGTGAAATCCCCGGGCTCAACCTGGGAA CTGCATCTGATACTGGCAAGCTTGAG 2948395 2948395 GTTGGAAGCCTTGAGCTTTTAGTGGCGCAGCTAACGCATTAA GTTGACCGCCTGGGGAGTACGGCCGCAAGGTTAAAACTCAA ATGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGT TTAATTCGAAAGATCGGAAGAGCGTC 2948395 2948395 TGTGCTCTTCCGATCTGTTGGAAGCCTTGAGCTTTTAGTGGC GCAGCTAACGCATTAAGTTGACCGCCTGGGGAGTACGGCCG CAAGGTTAAAACTCAAATGAATTGACGGGGGCCCGCACAAG CGGTGGAGCATGTGGTTTAATTCGAA 2948482 2948504 GTTTAATTCGATGCAACGCGAAGAACCTTACCTGGTCTTGAC ATCCACGGAAGTTTTCAGAGATGAGAATGTGCCTTCGGGAAC CGTGAGACAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGT GAAATGTTGGGTTAAGTCCCGCAAC 2948504 2948492 GCAACGCGAAGAACCTTACCTGGTCTTGAGATCCACGGAAG TTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACAG GTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGG GTTAAGTCCCGCAACGAGCGCAACCCG 2948544 2834049 ACACGCGTAAGAACACTCTTTCCCTACACGACGCTCTTCCGA TCTGTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGA CAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTT GGGTTAAGTCCCGCAACGAGCGCA 2948544 3077599 GTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAACGAGCGCAAGATCGGAAGAGCACACG TCTGAACTCCAGTCACAACCTACGATC 2948544 3117867 GTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAACGAGCGCAAGATCGGAAGAGCACACG TCTGAACTCCAGTCACAACCTACGATC 2948596 2948633 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCG CAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAG GTGGGGATGACGTCAAGTCATCATGG 2948633 2948596 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGT CCGGCCGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGA GGAAGGTGGGGATGACGTCAAGTCATCATGGCCCTTACGAC CAGGGCTACACACGTGCTACAATGGCG 2948646 2834151 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGG AACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGG GGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCGCATACAAAG 2948646 3077701 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACT CAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGGGGAT GACGTCAAGTCATCATGGCCCTTACGACCAGGGCTACACAC GTGCTACAATGGCGCATACAAAGAGAT 2948646 3117969 GCAACCGTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACT CAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGGGGAT GACGTCAAGTCATCATGGCCCTTACGACCAGGGCTACACAC GTGCTACAATGGCGCATACAAAGAGAT 2948804 2948804 GCGAGAGCAAGCGGACCTCATAAAGTGCGTCGTAGTCCGGA TTGGAGTCTGCAACTCGACTCCATGAAGTCGGAATCGCTAGT AATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCC TTGAGATCGGAAGAGCGTCGTGTAGG 2948804 2948804 TCAGACGTGTGCTCTTCCGATCTGCGAGAGCAAGCGGACCT CATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGA CTCCATGAAGTCGGAATCGCTAGTAATCGTGGATCAGAATGC CACGGTGAATACGTTCCCGGGCCTTG 2949540 2949540 CGGCGATTTCCGAATGGGGAAACCCAGTGTGTTTCGACACA CTATCATTAACTGAATCCATAGGTTAATGAGGCGAACCGGGG GAACTGAAACATCTAAGTACCCCGAGGAAAAGAAATCAACCG AGATTCCAGATCGGAAGAGCGTCGT 2949540 2949540 CGTGTGCTCTTCCGATCTCGGCGATTTCCGAATGGGGAAAC CCAGTGTGTTTCGACACACTATCATTAACTGAATCCATAGGTT AATGAGGCGAACCGGGGGAACTGAAACATCTAAGTACCCCG AGGAAAAGAAATCAACCGAGATTCC 2949652 2949652 AAGAAATCAACCGAGATTCCCCCAGTAGCGGCGAGCGAACG GGGAGGAGCCCAGAGCCTGAATCAGTGTGTGTGTTAGTGGA AGCGTCTGGAAAGGCGCGCGATACAGGGTGACAGCCCCGT ACACAAAAAAGATCGGAAGAGCGTCGTG 2949652 2949652 ACGTGTGCTCTTCCGATCTAAGAAATCAACCGAGATTCCCCC AGTAGCGGCGAGCGAACGGGGAGGAGCCCAGAGCCTGAAT CAGTGTGTGTGTTAGTGGAAGCGTCTGGAAAGGCGCGCGAT ACAGGGTGACAGCCCCGTACACAAAAA 2949922 2949958 GGCGAGGGGAGTGAAAAAGAACCTGAAACCGTGTACGTACA AGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACCTTTTGT ATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTAACCGA ATAGGGGAGCCGAAGGGAAACCGAG 2949958 2949922 GTACAAGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACC TTTTGTATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTA ACCGAATAGGGGAGCCGAAGGGAAACCGAGTCTTAACTGGG CGTTAAGTTGCAGGGTATAGACCCG 2950258 2950279 ATTTAGGTAGCGCCTCGTGAATTCATCTCCGGGGGTAGAGC ACTGTTTCGGCAAGGGGGTCATCCCGACTTACCAACCCGAT GCAAACTGCGAATACCGGAGAATGTTATCACGGGAGACACA CGGCGGGTGCTAACGTCCGTCGTGAAG 2950271 2835778 ATCTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCA AGGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAA TACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCT ACGTCCGTCGTGAAGAGGGAAACAAC 2950271 2835778 CTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAA GGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAAT ACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAA CGTCCGTCGTGAAGAGGGAAACAACCC 2950273 3079417 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACAGAT 2950273 3119594 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACAGAT 2950273 3079417 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACCCAG 2950273 3119594 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACCCAG 2950279 2950258 TTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGGGGGTCA TCCCGACTTACCAACCCGATGCAAACTGCGAATACCGGAGA ATGTTATCACGGGAGACACACGGCGGGTGCTAACGTCCGTC GTGAAGAGGGAAACAACCCAGACCGCC 2950897 2950897 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATAGATCGGAAGAGCAC 2950897 2950897 ACGCTCTTCCGATCTGTTTAAGCGTGTAGGCTGGTTTTCCAG GCAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCA CTACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAG CCTCTAAGCATCAGGTAACATCAAAT 2950897 2950925 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATCGTACCCCAAACCGA 2950925 2950897 CAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCAC TACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAGC CTCTAAGCATCAGGTAACATCAAATCGTACCCCAAACCGACA CAGGTGGTCAGGTAGAGAATACCAAG 2952041 2952127 GGTCCCTATCTGCCGTGGGCGCTGGAGAACTGAGGGGGGC TGCTCCTAGTACGAGAGGACCGGAGTGGACGCATCACTGGT GTTCGGGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAAT GCGGAAGAGATAAGTGCTGAAAGCATCT 2952127 2952041 GGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAATGCGGA AGAGATAAGTGCTGAAAGCATCTAAGCACGAAACTTGCCCCG AGATGAGTTCTCCCTGACTCCTTGAGAGTCCTGAAGGAACGT TGAAGACGACGACGTTGATAGGCCG 3028158 3028470 AGATTTCGTTGCTTTTTCCGTGAGGTGCTCTTTTTTCGCCGC GAAGGTGCCGGTTGGCTGCGGCGTACATAATCTCGTTGTGC CACTATCGTTTCGCTGTATTTATTCGTTCGTCAGCCCGCCAT GTTACTTAAGCGGCGGGCCTTTGAC 3028158 3028470 AGATTTCGTTGCTTTTTCCGTGAGGTGCTCTTTTTTCGCCGC GAAGGTGCCGGTTGGCTGCGGCGTACATAATCTCGTTGTGC CACTATCGTTTCGCTGTATTTATTCGTTCGTCAGCCCGCCAT GTTACTTAAGCGGCGGGCCTTTGAC 3028470 3028158 CGCGATGGTTGTCAGCGGCGGATCACAAAATTGCGTCAGGT CGATGTTATCAAAACCGATTATGGAAAGGTCTTCCGGGACTT TCAGCCCCTGGCGTTTTGCCTGAGAAAGTGCGCCGAGCGCC ATCACATCGCTATGGCAGAAGACAGC 3028470 3028158 CGCGATGGTTGTCAGCGGCGGATCACAAAATTGCGTCAGGT CGATGTTATCAAAACCGATTATGGAAAGGTCTTCCGGGACTT TCAGCCCCTGGCGTTTTGCCTGAGAAAGTGCGCCGAGCGCC ATCACATCGCTATGGCAGAAGACAGC 3076616 3076622 CTCAGATTGAACGCTGGCGGCAGGCCTAACACATGCAAGTC GAACGGTAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTG GCGGACGGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGG GGGATAACTACTGGAAACGGTAGCTAA 3076622 3076616 TTGAACGCTGGCGGCAGGCCTAACACATGCAAGTCGAACGG TAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTGGCGGAC GGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGGGGGATA ACTACTGGAAACGGTAGCTAATACCGC 3076826 3076832 CCCAGATGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCT AGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCAC ACTGGAACTGAGACACGGTCCAGACTCCTACGGGAGGCAGC AGTGGGGAATATTGCACAATGGGCGCA 3076832 3076826 TGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCTAGGCGA CGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGA ACTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGG GGAATATTGCACAATGGGCGCAAGCCTG 3077061 3077100 ACCTTTGCTCATTGACGTTACCCGCAGAAGAAGCAGCGGCTA ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAAGC GTTAATCGGAATTAGTGGGCGTAAAGCGCACGCAGGCGGTT TGTTAAGTCAGATGTGAAATCCCCGGG 3077100 3077061 CTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAA GCGTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGG TTTGTTAAGTCAGATGTGAAATCCCCGGGCTCAACCTGGGAA CTGCATCTGATACTGGCAAGCTTGAG 3077547 3077559 GTTTAATTCGATGCAACGCGAAGAACCTTACCTGGTCTTGAC ATCCACGGAAGTTTTCAGAGATGAGAATGTGCCTTCGGGAAC CGTGAGACAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGT GAAATGTTGGGTTAAGTCCCGCAAC 3077559 3077547 GCAACGCGAAGAACCTTACCTGGTCTTGACATCCACGGAAG TTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACAG GTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGG GTTAAGTCCCGCAACGAGCGCAACCCG 3077599 3117867 GTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAACGAGCGCAAGATCGGAAGAGCACACG TCTGAACTCCAGTCACAACCTACGATC 3077599 2948544 ACACGCGTAAGAACACTCTTTCCCTACACGACGCTCTTCCGA TCTGTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGA CAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTT GGGTTAAGTCCCGCAACGAGCGCA 3077599 2834049 ACACGCGTAAGAACACTCTTTCCCTACACGACGCTCTTCCGA TCTGTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGA CAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTT GGGTTAAGTCCCGCAACGAGCGCA 3077651 3077688 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCG CAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAG GTGGGGATGACGTCAAGTCATCATGG 3077688 3077651 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGT CCGGCCGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGA GGAAGGTGGGGATGACGTCAAGTCATCATGGCCCTTACGAC CAGGGCTACACACGTGCTACAATGGCG 3077701 3117969 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGGAACT CAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGGGGAT GACGTCAAGTCATCATGGCCCTTACGACCAGGGCTACACAC GTGCTACAATGGCGCATACAAAGAGAT 3077701 2948646 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGG AACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGG GGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCGCATACAAAG 3077701 2834151 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGG AACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGG GGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAA.TGGCGCATACAAAG 3077859 3077859 GCGAGAGCAAGCGGACCTCATAAAGTGCGTCGTAGTCCGGA TTGGAGTCTGCAACTCGACTCCATGAAGTCGGAATCGCTAGT AATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCC TTGAGATCGGAAGAGCGTCGTGTAGG 3077859 3077859 TCAGACGTGTGCTCTTCCGATCTGCGAGAGCAAGCGGACCT CATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGA CTCCATGAAGTCGGAATCGCTAGTAATCGTGGATCAGAATGC CACGGTGAATACGTTCCCGGGCCTTG 3078686 3078686 CGGCGATTTCCGAATGGGGAAACCCAGTGTGTTTCGACACA CTATCATTAACTGAATCCATAGGTTAATGAGGCGAACCGGGG GAACTGAAACATCTAAGTACCCCGAGGAAAAGAAATCAACCG AGATTCCAGATCGGAAGAGCGTCGT 3078686 3078686 CGTGTGCTCTTCCGATCTCGGCGATTTCCGAATGGGGAAAC CCAGTGTGTTTCGACACACTATCATTAACTGAATCCATAGGTT AATGAGGCGAACCGGGGGAACTGAAACATCTAAGTACCCCG AGGAAAAGAAATCAACCGAGATTCC 3078798 3078798 AAGAAATCAACCGAGATTCCCCCAGTAGCGGCGAGCGAACG GGGAGGAGCCCAGAGCCTGAATCAGTGTGTGTGTTAGTGGA AGCGTCTGGAAAGGCGCGCGATACAGGGTGACAGCCCCGT ACACAAAAAAGATCGGAAGAGCGTCGTG 3078798 3078798 ACGTGTGCTCTTCCGATCTAAGAAATCAACCGAGATTCCCCC AGTAGCGGCGAGCGAACGGGGAGGAGCCCAGAGCCTGAAT CAGTGTGTGTGTTAGTGGAAGCGTCTGGAAAGGCGCGCGAT ACAGGGTGACAGCCCCGTACACAAAAA 3079068 3079104 GGCGAGGGGAGTGAAAAAGAACCTGAAACCGTGTACGTACA AGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACCTTTTGT ATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTAACCGA ATAGGGGAGCCGAAGGGAAACCGAG 3079104 3079068 GTACAAGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACC TTTTGTATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTA ACCGAATAGGGGAGCCGAAGGGAAACCGAGTCTTAACTGGG CGTTAAGTTGCAGGGTATAGACCCG 3079404 3079425 ATTTAGGTAGCGCCTCGTGAATTCATCTCCGGGGGTAGAGC ACTGTTTCGGCAAGGGGGTCATCCCGACTTACCAACCCGAT GCAAACTGCGAATACCGGAGAATGTTATCACGGGAGACACA CGGCGGGTGCTAACGTCCGTCGTGAAG 3079417 2950273 ATCTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCA AGGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAA TACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTA ACGTCCGTCGTGAAGAGGGAAACAAC 3079417 2835778 ATCTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTGGGCA AGGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAA TACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTA ACGTCCGTCGTGAAGAGGGAAACAAC 3079417 2950273 CTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAA GGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAAT ACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAA CGTCCGTCGTGAAGAGGGAAACAACCC 3079417 2835778 CTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAA GGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAAT ACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAA CGTCCGTCGTGAAGAGGGAAACAACCC 3079419 3119594 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACAGAT 3079419 3119594 CGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGG GGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAATAC CGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAACG TCCGTCGTGAAGAGGGAAACAACCCAG 3079425 3079404 TTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGGGGGTCA TCCCGACTTACCAACCCGATGCAAACTGCGAATACCGGAGA ATGTTATCACGGGAGACACACGGCGGGTGCTAACGTCCGTC GTGAAGAGGGAAACAACCCAGACCGCC 3080043 3080043 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATAGATCGGAAGAGCAC 3080043 3080043 ACGCTCTTCCGATCTGTTTAAGCGTGTAGGCTGGTTTTCCAG GCAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCA CTACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAG CCTCTAAGCATCAGGTAACATCAAAT 3080043 3080071 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATCGTACCCCAAACCGA 3080071 3080043 CAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCAC TACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAGC CTCTAAGCATCAGGTAACATCAAATCGTACCCCAAACCGACA CAGGTGGTCAGGTAGAGAATACCAAG 3081187 3081273 GGTCCCTATCTGCCGTGGGCGCTGGAGAACTGAGGGGGGC TGCTCCTAGTACGAGAGGACCGGAGTGGACGCATCACTGGT GTTCGGGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAAT GCGGAAGAGATAAGTGCTGAAAGCATCT 3081273 3081187 GGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAATGCGGA AGAGATAAGTGCTGAAAGCATCTAAGCACGAAACTTGCCCCG AGATGAGTTCTCCCTGACTCCTTGAGAGTCCTGAAGGAACGT TGAAGACGACGACGTTGATAGGCCG 3116884 3116890 CTCAGATTGAACGCTGGCGGCAGGCCTAACACATGCAAGTC GAACGGTAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTG GCGGACGGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGG GGGATAACTACTGGAAACGGTAGCTAA 3116890 3116884 TTGAACGCTGGCGGCAGGCCTAACACATGCAAGTCGAACGG TAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTGGCGGAC GGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGGGGGATA ACTACTGGAAACGGTAGCTAATACCGC 3117094 3117100 CCCAGATGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCT AGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCAC ACTGGAACTGAGACACGGTCCAGACTCCTACGGGAGGCAGC AGTGGGGAATATTGCACAATGGGCGCA 3117100 3117094 TGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCTAGGCGA CGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGA ACTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGG GGAATATTGCACAATGGGCGCAAGCCTG 3117329 3117368 ACCTTTGCTCATTGACGTTACCCGCAGAAGAAGCACCGGCTA ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAAGC GTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGGTT TGTTAAGTCAGATGTGAAATCCCCGGG 3117368 3117329 CTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAA GCGTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGG TTTGTTAAGTCAGATGTGAAATCCCCGGGCTCAACCTGGGAA CTGCATCTGATACTGGCAAGCTTGAG 3117718 3117718 GTTGGAAGCCTTGAGCTTTTAGTGGCGCAGCTAACGCATTAA GTTGACCGCCTGGGGAGTACGGCCGCAAGGTTAAAACTCAA ATGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGT TTAATTCGAAAGATCGGAAGAGCGTC 3117718 3117718 TGTGCTCTTCCGATCTGTTGGAAGCCTTGAGCTTTTAGTGGC GCAGCTAACGCATTAAGTTGACCGCCTGGGGAGTACGGCCG CAAGGTTAAAACTCAAATGAATTGACGGGGGCCCGCACAAG CGGTGGAGCATGTGGTTTAATTCGAA 3117815 3117827 GTTTAATTCGATGCAACGCGAAGAACCTTACCTGGTCTTGAC ATCCACGGAAGTTTTCAGAGATGAGAATGTGCCTTCGGGAAC CGTGAGACAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGT GAAATGTTGGGTTAAGTCCCGCAAC 3117827 3117815 GCAACGCGAAGAACCTTACCTGGTCTTGACATCCACGGAAG TTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGACAG GTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGG GTTAAGTCCCGCAACGAGCGCAACCCG 3117867 3077599 ACACGCGTAAGAACACTCTTTCCCTAGACGACGCTCTTCCGA TCTGTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGA CAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTT GGGTTAAGTCCCGCAACGAGCGCA 3117867 2948544 ACACGCGTAAGAACACTCTTTCCCTACACGACGCTCTTCCGA TCTGTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGA CAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTT GGGTTAAGTCCCGCAACGAGCGCA 3117867 2834049 ACACGCGTAAGAACACTCTTTCCCTACACGACGCTCTTCCGA TCTGTTTTCAGAGATGAGAATGTGCCTTCGGGAACCGTGAGA CAGGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTT GGGTTAAGTCCCGCAACGAGCGCA 3117919 3117956 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCG CAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAG GTGGGGATGACGTCAAGTCATCATGG 3117956 3117919 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGT CCGGCCGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGA GGAAGGTGGGGATGACGTCAAGTCATCATGGCCCTTACGAC CAGGGCTACACACGTGCTACAATGGCG 3117969 3077701 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGG AACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGG GGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCGCATACAAAG 3117969 2948646 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGG AACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGG GGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCGCATACAAAG 3117969 2834151 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGCCGGG AACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAGGTGG GGATGACGTCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCGCATACAAAG 3118127 3118127 GCGAGAGCAAGCGGACCTCATAAAGTGCGTCGTAGTCCGGA TTGGAGTCTGCAACTCGACTCCATGAAGTCGGAATCGCTAGT AATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCC TTGAGATCGGAAGAGCGTCGTGTAGG 3118127 3118127 TCAGACGTGTGCTCTTCCGATCTGCGAGAGCAAGCGGACCT CATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGA CTCCATGAAGTCGGAATCGCTAGTAATCGTGGATCAGAATGC CACGGTGAATACGTTCCCGGGCCTTG 3118863 3118863 CGGCGATTTCCGAATGGGGAAACCCAGTGTGTTTCGACACA CTATCATTAACTGAATCCATAGGTTAATGAGGCGAACCGGGG GAACTGAAACATCTAAGTACCCCGAGGAAAAGAAATCAACCG AGATTCCAGATCGGAAGAGCGTCGT 3118863 3118863 CGTGTGCTCTTCCGATCTCGGCGATTTCCGAATGGGGAAAC CCAGTGTGTTTCGACACACTATCATTAACTGAATCCATAGGTT AATGAGGCGAACCGGGGGAACTGAAACATCTAAGTACCCCG AGGAAAAGAAATCAACCGAGATTCC 3118975 3118975 AAGAAATCAACCGAGATTCCCCCAGTAGCGGCGAGCGAACG GGGAGGAGCCCAGAGCCTGAATCAGTGTGTGTGTTAGTGGA AGCGTCTGGAAAGGCGCGCGATACAGGGTGACAGCCCCGT ACACAAAAAAGATCGGAAGAGCGTCGTG 3118975 3118975 ACGTGTGCTCTTCCGATCTAAGAAATCAACCGAGATTCCCCC AGTAGCGGCGAGCGAACGGGGAGGAGCCCAGAGCCTGAAT CAGTGTGTGTGTTAGTGGAAGCGTCTGGAAAGGCGCGCGAT ACAGGGTGACAGCCCCGTACACAAAAA 3119245 3119281 GGCGAGGGGAGTGAAAAAGAACCTGAAACCGTGTACGTACA AGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACCTTTTGT ATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTAACCGA ATAGGGGAGCCGAAGGGAAACCGAG 3119281 3119245 GTACAAGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACC TTTTGTATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTA ACCGAATAGGGGAGCCGAAGGGAAACCGAGTCTTAACTGGG CGTTAAGTTGCAGGGTATAGACCCG 3119581 3119602 ATTTAGGTAGCGCCTCGTGAATTCATCTCCGGGGGTAGAGC ACTGTTTCGGCAAGGGGGTCATCCCGACTTACCAACCCGAT GCAAACTGCGAATACCGGAGAATGTTATCACGGGAGACACA CGGCGGGTGCTAACGTCCGTCGTGAAG 3119594 3079419 ATCTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCA AGGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAA TACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTA ACGTCCGTCGTGAAGAGGGAAACAAC 3119594 2950273 ATCTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCA AGGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAA TACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTA ACGTCCGTCGTGAAGAGGGAAACAAC 3119594 2835778 ATCTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCA AGGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAA TACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTA ACGTCCGTCGTGAAGAGGGAAACAAC 3119594 3079419 CTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAA GGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAAT ACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAA CGTCCGTCGTGAAGAGGGAAACAACCC 3119594 2950273 CTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAA GGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAAT ACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAA CGTCCGTCGTGAAGAGGGAAACAACCC 3119594 2835778 CTCGTGAATTCATCTCCGGGGGTAGAGCACTGTTTCGGCAA GGGGGTCATCCCGACTTACCAACCCGATGCAAACTGCGAAT ACCGGAGAATGTTATCACGGGAGACACACGGCGGGTGCTAA CGTCCGTCGTGAAGAGGGAAACAACCC 3119602 3119581 TTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGGGGGTCA TCCCGACTTACCAACCCGATGCAAACTGCGAATACCGGAGA ATGTTATCACGGGAGACACACGGCGGGTGCTAACGTCCGTC GTGAAGAGGGAAACAACCCAGACCGCC 3120220 3120220 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATAGATCGGAAGAGCAC 3120220 3120220 ACGCTCTTCCGATCTGTTTAAGCGTGTAGGCTGGTTTTCCAG GCAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCA CTACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAG CCTCTAAGCATCAGGTAACATCAAAT 3120220 3120248 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATCGTACCCCAAACCGA 3120248 3120220 CAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCAC TACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAGC CTCTAAGCATCAGGTAACATCAAATCGTACCCCAAACCGACA CAGGTGGTCAGGTAGAGAATACCAAG 3121364 3121450 GGTCCCTATCTGCCGTGGGCGCTGGAGAACTGAGGGGGGC TGCTCCTAGTACGAGAGGACCGGAGTGGACGCATCACTGGT GTTCGGGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAAT GCGGAAGAGATAAGTGCTGAAAGCATCT 3121450 3121364 GGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAATGCGGA AGAGATAAGTGCTGAAAGCATCTAAGCACGAAACTTGCCCCG AGATGAGTTCTCCCTGACTCCTTGAGAGTCCTGAAGGAACGT TGAAGACGACGACGTTGATAGGCCG 3991338 3991487 CGACGCGTAATGCGTTGGGGATTCTTGGTGGGATCCCGCGC CGTGAATTTACTCGCGACAGCATCGAAGAGAAAGTCGCTGC CACCACGCAGGCACAATGGCCGGTTCATGCGGTGATTACCA ACTCCACCTATGATGGCTTGCTCTACA 3991487 3991338 AACACCGACTGGATCAAACAGACGCTGGATGTCCCGTCGAT CCACTTCGATTCCGCCTGGGTGCCGTACACCCATTTTCATCC GATCTACCAGGGGAAAAGTGGTATGAGCGGCGAGCGTGTTG CGGGAAAAGTGATCTTCGAAACGCAA 4004615 4004621 CTCAGATTGAACGCTGGCGGCAGGCCTAACACATGCAAGTC GAACGGTAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTG GCGGACGGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGG GGGATAACTACTGGAAACGGTAGCTAA 4004621 4004615 TTGAACGCTGGCGGCAGGCCTAACACATGCAAGTCGAACGG TAACAGGAAGCAGCTTGCTGCTTTGCTGACGAGTGGCGGAC GGGTGAGTAATGTCTGGGAAACTGCCTGATGGAGGGGGATA ACTACTGGAAACGGTAGCTAATACCGC 4004825 4004831 CCCAGATGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCT AGGCGACGATCCCTAGCTGGTCTGAGAGGATGACCAGCCAC ACTGGAACTGAGACACGGTCCAGACTCCTACGGGAGGCAGC AGTGGGGAATATTGCACAATGGGCGCA 4004831 4004825 TGGGATTAGCTAGTAGGTGGGGTAACGGCTCACCTAGGCGA CGATCCCTAGCTGGTCTGAGAGGATGACCAGCCACACTGGA ACTGAGACACGGTCCAGACTCCTACGGGAGGCAGCAGTGG GGAATATTGCACAATGGGCGCAAGCCTG 4005060 4005099 ACCTTTGCTCATTGACGTTACCCGCAGAAGAAGCACCGGCTA ACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAAGC GTTAATCGGAATTACTGGGCGTAAA.GCGCACGCAGGCGGTT TGTTAAGTCAGATGTGAAATCCCCGGG 4005099 4005060 CTAACTCCGTGCCAGCAGCCGCGGTAATACGGAGGGTGCAA GCGTTAATCGGAATTACTGGGCGTAAAGCGCACGCAGGCGG TTTGTTAAGTCAGATGTGAAATCCCCGGGCTCAACCTGGGAA CTGCATCTGATACTGGCAAGCTTGAG 4005449 4005449 GTTGGAAGCCTTGAGCTTTTAGTGGCGCAGCTAACGCATTAA GTTGACCGCCTGGGGAGTACGGCCGCAAGGTTAAAACTCAA ATGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTGGT TTAATTCGAAAGATCGGAAGAGCGTC 4005449 4005449 TGTGCTCTTCCGATCTGTTGGAAGCCTTGAGCTTTTAGTGGC GCAGCTAACGCATTAAGTTGACCGCCTGGGGAGTACGGCCG CAAGGTTAAAACTCAAATGAATTGACGGGGGCCCGCACAAG CGGTGGAGCATGTGGTTTAATTCGAA 4005598 4005598 GTTfTCAGAGATGAGAATGTGCCTTCGGGAGCCGTGAGACA GGTGCTGCATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGGAACGAGCGGAACGCTTATCCAGATCGGA AGAGCACACGTCTGAACTCCAGTCACA 4005598 4005598 GAACACTCTTTCCCTACACGACGCTCTTCCGATCTGTTTTCA GAGATGAGAATGTGCCTTCGGGAGCCGTGAGACAGGTGCTG CATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGT CCCGCAACGAGCGCAACCCTTATCC 4005650 4005687 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCCCG CAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGAGGAAG GTGGGGATGACGTCAAGTCATCATGG 4005687 4005650 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGCCAGCGGT CCGGCCGGGAACTCAAAGGAGACTGCCAGTGATAAACTGGA GGAAGGTGGGGATGACGTCAAGTCATCATGGCCCTTACGAC CAGGGCTACACACGTGCTACAATGGCG 4005858 4005858 GCGAGAGCAAGCGGACCTCATAAAGTGCGTCGTAGTCCGGA TTGGAGTCTGCAACTCGACTCCATGAAGTCGGAATCGCTAGT AATCGTGGATCAGAATGCCACGGTGAATACGTTCCCGGGCC TTGAGATCGGAAGAGCGTCGTGTAGG 4005858 4005858 TCAGACGTGTGCTCTTCCGATCTGCGAGAGCAAGCGGACCT CATAAAGTGCGTCGTAGTCCGGATTGGAGTCTGCAACTCGA CTCCATGAAGTCGGAATCGCTAGTAATCGTGGATCAGAATGC CACGGTGAATACGTTCCCGGGCCTTG 4006607 4006670 GATGCCCTGGCAGTCAGAGGCGATGAAGGACGTGCTAATCT GCGATAAGCGTCGGTGAGGTGATATGAACCGTTATAACCGG CGATTTCCGAATGGGGAAACCCAGTGTGATTCGTCACACTAT CATTAACTGAATCCATAGGTTAATGA 4006670 4006607 TATGAACCGTTATAACCGGCGATTTCCGAATGGGGAAACCCA GTGTGATTCGTCACACTATCATTAACTGAATCCATAGGTTAAT GAGGCGAACCGGGGGAACTGAAACATCTAAGTACCCCGAGG AAAAGAAATCAACCGAGATTCCCC 4006798 4006798 AAGAAATCAACCGAGATTCCCCCAGTAGCGGCGAGCGAACG GGGAGGAGCCCAGAGCCTGAATCAGTGTGTGTGTTAGTGGA AGCGTCTGGAAAGGCGCGCGATACAGGGTGACAGCCCCGT ACACAAAAAAGATCGGAAGAGCGTCGTG 4006798 4006798 ACGTGTGCTCTTCCGATCTAAGAAATCAACCGAGATTCCCCC AGTAGCGGCGAGCGAACGGGGAGGAGCCCAGAGCCTGAAT CAGTGTGTGTGTTAGTGGAAGCGTCTGGAAAGGCGCGCGAT ACAGGGTGACAGCCCCGTACACAAAAA 4007068 4007104 GGCGAGGGGAGTGAAAAAGAACCTGAAACCGTGTACGTACA AGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACCTTTTGT ATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTAACCGA ATAGGGGAGCCGAAGGGAAACCGAG 4007104 4007068 GTACAAGCAGTGGGAGCCTCTTAATGGGGTGACTGCGTACC TTTTGTATAATGGGTCAGCGACTTATATTCTGTAGCAAGGTTA ACCGAATAGGGGAGCCGAAGGGAAACCGAGTCTTAACTGGG CGTTAAGTTGCAGGGTATAGACCCG 4007404 4007425 ATTTAGGTAGCGCCTCGTGAATTCATCTCCGGGGGTAGAGC ACTGTTTCGGCAAGGGGGTCATCCCGACTTACCAACCCGAT GCAAACTGCGAATACCGGAGAATGTTATCACGGGAGACACA CGGCGGGTGCTAACGTCCGTCGTGAAG 4007425 4007404 TTCATCTCCGGGGGTAGAGCACTGTTTCGGCAAGGGGGTCA TCCCGACTTACCAACCCGATGCAAACTGCGAATACCGGAGA ATGTTATCACGGGAGACACACGGCGGGTGCTAACGTCCGTC GTGAAGAGGGAAACAACCCAGACCGCC 4008043 4008043 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATAGATCGGAAGAGCAC 4008043 4008043 ACGCTCTTCCGATCTGTTTAAGCGTGTAGGCTGGTTTTCCAG GCAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCA CTACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAG CCTCTAAGCATCAGGTAACATCAAAT 4008043 4008071 GTTTAAGCGTGTAGGCTGGTTTTCCAGGCAAATCCGGAAAAT CAAGGCTGAGGCGTGATGACGAGGCACTACGGTGCTGAAGC GACAAATGCCCTGCTTCCAGGAAAAGCCTCTAAGCATCAGGT AACATCAAATCGTACCCCAAACCGA 4008071 4008043 CAAATCCGGAAAATCAAGGCTGAGGCGTGATGACGAGGCAC TACGGTGCTGAAGCGACAAATGCCCTGCTTCCAGGAAAAGC CTCTAAGCATCAGGTAACATCAAATCGTACCCCAAACCGACA CAGGTGGTCAGGTAGAGAATACCAAG 4009187 4009273 GGTCCCTATCTGCCGTGGGCGCTGGAGAACTGAGGGGGGC TGCTCCTAGTACGAGAGGACCGGAGTGGACGCATCACTGGT GTTCGGGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAAT GCGGAAGAGATAAGTGCTGAAAGCATCT 4009273 4009187 GGTTGTCATGCCAATGGCACTGCCCGGTAGCTAAATGCGGA AGAGATAAGTGCTGAAAGCATCTAAGCACGAAACTTGCCCCG AGATGAGTTCTCCCTGACTCCTTGAGAGTCCTGAAGGAACGT TGAAGACGACGACGTTGATAGGCCG 4527988 4527990 TTCCCTACACGACGCTCTTCCGATCTCGCCACATGATGATGG ATTTTGGCTATCTGGAAGAAACATTCGAAGCGGGTAAACGCT CAGCCAAAATCTCCTTTGTTATTACTGTCGTGCTTTCACTTCT CGCAGGAGTCCTCGTATGGTAAG 4527990 4527988 CTCCACATGATGATGGATTTTGGCTATCTGGAAGAAACATTC GAAGAGGGTAAACGATCCGCCAAAATCTCCTTTGTTATTACT GTCGTGATTTCACTTCTCGCAGGAGTCATCTTATGTTAAGAG ATCGGAAGAGCACACGTCTGAACT

Next, target genes were identified to create custom PCR primers for identification of the pathogen. See TABLE 8.

TABLE 8 Target genes wcaK Start End Nucleic Acid Sequence A01587:71 2317120 2317148 CTTGGTATTCTCTACCTGACCACCTGTGTCGGTT TGGGGTACGATTTGATGTTACCTGATGCTTAGAG GCTTTTCCTGGAAGCAGGGCATTTGTCGCTTCA GCACCGTAGTGCCTCGICATCACGCCTCAGCCT TGATTTTCCGGATTTG A01587:71 2317148 2317120 TCGGTTTGGGGTACGATTTGATGTTACCTGATGC TTAGAGGCTTTTCCTGGAAGCAGGGCATTTGTC GCTTCAGCACCGTAGTGCCTCGTCATCACGCCT CAGCCTTGATTTTCCGGATTTGCCTGGAAAACCA GCCTACACGCTTAAAC A01587:71 2317163 2317163 ATTTGATGITACCTGATGCTTAGAGGCTTTTCCT GGAAGCAGGGCATTTGTCGCTTCAGCACCGTAG TGCCTCGTCATCACGCCTCAGCCTTGATTTTCCG GATTTGCCTGGAAAACCAGCCTACACGCTTAAAC AGATCGGAAGAGCGT A01587:71 2317163 2317163 GTGCTCTTCCGATCTATTTGATGTTACCTGATGC TTAGAGGCTTTTCCTGGAAGCAGGGCATTTGTC GCTTCAGCACCGTAGTGCCTCGTCATCACGCCT CAGCCTTGATTTTCCGGATTTGCCTGGAAAACCA GCCTACACGCTTAAAC wcaJ Start End Nucleic Acid Sequence A01587:71 2319355 2319355 CAAGGCCCGGGAACGTATTCACCGTGGCATTCT GATCCACGATTACTAGCGATTCCGACTTCATGGA GTCGAGTTGCAGACTCCAATCCGGACTACGACG CACTTTATGAGGTCCGCTTGCTCTCGCAGATCG GAAGAGCACACGTCTGA A01587:71 2319355 2319355 CCTACACGACGCTCTTCCGATCTCAAGGCCCGG GAACGTATTCACCGTGGCATTCTGATCCACGATT ACTAGCGATTCCGACTTCATGGAGTCGAGTTGC AGACTCCAATCCGGACTACGACGCACTTTATGA GGTCCGCTTGCTCTCGC A01587:71 2319362 1503671 CTGGAGTTCAGACGTGTGCTCTTCCGATCTCGG GAACGTATTCACCGTGGCATTCTGATCCACGATT ACTAGCGATTCCGACTTCATGGAGTCGAGTTGC AGACTCCAATCCGGACTACGACGCACTTTATGA GGTCCGCTTGCTCTCGC A01587:71 2319503 2319540 CGCCATTGTAGCACGTGTGTAGCCCTGGTCGTA AGGGCCATGATGACTTGACGTCATCCCCACCTT CCTCCAGTTTATCACTGGCAGTCTCCTTTGAGTT CCCGGCCGGACCGCTGGCAACAAAGGATAAGG GTTGCGCTCGTTGCGGGA A01587:71 2319540 2319503 CCATGATGACTTGACGTCATCCCCACCTTCCTCC AGTTTATCACTGGCAGTCTCCTTTGAGTTCCCGG CCGGACCGCTGGCAACAAAGGATAAGGGTTGCG CTCGTTGCGGGACTTAACCCAACATTTCACAACA CGAGCTGACGACAGC A01587:71 2319633 2319644 CGGGTTGCGCTCGTTGCGGGACTTAACCCAACA TTTCACAACACGAGCTGACGACAGCCATGCAGC ACCTGTCTCACGGTTCCCGAAGGCACATTCTCAT CTCTGAAAACTTCCGTGGATGTCAAGACCAGGTA AGGTTCTTCGCGTTGC A01587:71 2319644 2319633 GTTGCGGGACTTAACCCAACATTTCACAACACGA GCTGACGACAGCCATGCAGCACCTGTCTCACGG TTCCCGAAGGCACATTCTCATCTCTGAAAACTTC CGTGGATGTCAAGACCAGGTAAGGTTCTTCGCG TTGCATCGAATTAAAC A01587:71 2319783 2319783 TTCGAATTAAACCACATGCTCCACCGCTTGTGCG GGCCCCCGTCAATTCATTTGAGTTTTAACCTTGC GGCCGTACTCCCCAGGCGGTCAACTTAATGCGT TAGCTGCGCCACTAAAAGCTCAAGGCTTCCAAC AGATCGGAAGAGCACA A01587:71 2319783 2319783 GACGCTCTTCCGATCTTTCGAATTAAACCACATG CTCCACCGCTTGTGCGGGCCCCCGTCAATTCAT TTGAGTTTTAACCTTGCGGCCGTACTCCCCAGG CGGTCAACTTAATGCGTTAGCTGCGCCACTAAAA GCTCAAGGCTTCCAAC fdx Star End Nucleic Acid Sequence A01587:71 2833900 2833900 GTTGGAAGCCTTGAGCTTTTAGTGGCGCAGCTA ACGCATTAAGTTGACCGCCTGGGGAGTACGGCC GCAAGGTTAAAACTCAAATGAATTGACGGGGGC CCGCACAAGCGGTGGAGCATGTGGTTTAATTCG AAAGATCGGAAGAGCGTC A01687:71 2833900 2833900 TGTGCTCTTCCGATCTGTTGGAAGCCTTGAGCTT TTAGTGGCGCAGCTAACGCATTAAGTTGACCGC CTGGGGAGTACGGCCGCAAGGTTAAAACTCAAA TGAATTGACGGGGGCCCGCACAAGCGGTGGAG CATGTGGTTTAATTCGAA A01587:71 2833997 2834009 GTTTAATTCGATGCAACGCGAAGAACCTTACCTG GTCTTGACATCCACGGAAGTTTTCAGAGATGAGA ATGTGCCTTCGGGAACCGTGAGACAGGTGCTGC ATGGCTGTCGTCAGCTCGTGTTGTGAAATGTTG GGTTAAGTCCCGCAAC A01587:71 2834009 2833997 GCAACGCGAAGAACCTTACCTGGTCTTGACATC CACGGAAGTTTTGAGAGATGAGAATGTGCCTTC GGGAACCGTGAGACAGGTGCTGOATGGCTGTC GTCAGCTCGTGTTGTGAAATGTTGGGTTAAGTCC CGCAACGAGCGCAACCCG A01587:71 2834049 2948544 GTTTTGAGAGATGAGAATGTGCCTTCGGGAACC GTGAGACAGGTGCTGGATGGCTGTCGTCAGCTC GTGTTGTGAAATGTTGGGTTAAGTCCCGCAACG AGCGCAAGATGGGAAGAGCAGACGTCTGAACTC CAGTCACAACGTACGATC A01587:71 2834049 3077599 GTTTTGAGAGATGAGAATGTGCCTTCGGGAACC GTGAGACAGGTGCTGCATGGCTGTCGTCAGCTC GTGTTGTGAAATGTTGGGTTAAGTCCCGCAACG AGCGCAAGATCGGAAGAGCACACGTCTGAACTC CAGTCAGAAGGTACGATC A01587:71 2834049 3117867 GTTTTCAGAGATGAGAATGTGGGTTCGGGAACC GTGAGACAGGTGCTGCATGGCTGTCGTCAGCTC GTGTTGTGAAATGTTGGGTTAAGTCCCGCAACG AGCGCAAGATCGGAAGAGCAGACGTCTGAACTC CAGTCACAACCTACGATC A01587:71 2834101 2834138 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTT AAGTCCCGCAACGAGCGCAACCCTTATCCTTTGT TGCCAGCGGTCCGGCCGGGAACTCAAAGGAGA CTGCCAGTGATAAACTGGAGGAAGGTGGGGATG ACGTCAAGTCATCATGG A01587:71 2834138 2834101 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGC CAGCGGTCCGGCCGQGAACTCAAAGGAGACTG CCAGTGATAAACTGGAGGAAGGTGGGGATGACG TCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCG A01587:71 2834151 2948646 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACT GGAGGAAGGTGGGGATGACGTCAAGTCATCATG GCCCTTACGACCAGGGCTACACACGTGCTACAA TGGCGCATACAAAGAGAT A01587:71 2834151 3077701 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACT GGAGGAAGGTGGGGATGACGTCAAGTCATCATG GCCCTTACGACCAGGGCTACACACGTGCTACAA TGGCGCATACAAAGAGAT A01587:71 2834151 3117969 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACT GGAGGAAGGTGGGGATGACGTCAAGTCATCATG GCCCTTACGACCAGGGCTACACACGTGCTACAA TGGCGCATACAAAGAGAT ygaZ Start End Nucleic Acid Sequence A01587:71 2948596 2948633 GCTGTCGTCAGCTCGTGTTGTGAAATGTTGGGTT AAGTCCCGCAACGAGCGCAACCCTTATCCTTTGT TGCCAGCGGTCCGGCCGGGAACTCAAAGGAGA CTGCCAGTGATAAACTGGAGGAAGGTGGGGATG ACGTCAAGTCATCATGG A01587:71 2948633 2948596 TCCCGCAACGAGCGCAACCCTTATCCTTTGTTGC CAGCGGTCCGGCCGGGAACTCAAAGGAGACTG CCAGTGATAAACTGGAGGAAGGTGGGGATGACG TCAAGTCATCATGGCCCTTACGACCAGGGCTAC ACACGTGCTACAATGGCG A01587:71 2948646 2834151 ATCTGCAACCCTTATCCTTTGTTGCCAGCGGTCC GGCCGGGAACTCAAAGGAGACTGCCAGTGATAA ACTGGAGGAAGGTGGGGATGACGTCAAGTCATC ATGGCCCTTACGACCAGGGCTACACACGTGCTA CAATGGCGCATACAAAG A01587:71 2948646 3077701 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACT GGAGGAAGGTGGGGATGACGTCAAGTCATCATG GCCCTTACGACCAGGGCTACACACGTGCTACAA TGGCGCATACAAAGAGAT A01587:71 2948646 3117969 GCAACCCTTATCCTTTGTTGCCAGCGGTCCGGC CGGGAACTCAAAGGAGACTGCCAGTGATAAACT GGAGGAAGGTGGGGATGACGTCAAGTCATCATG GCCCTTACGACCAGGGCTACACACGTGCTACAA TGGCGCATACAAAGAGAT A01587:71 2948804 2948804 GCGAGAGCAAGCGGACCTCATAAAGTGCGTCGT AGTCCGGATTGGAGTCTGCAACTCGACTCCATG AAGTCGGAATCGCTAGTAATCGTGGATCAGAAT GCCACGGTGAATACGTTCCCGGGCCTTGAGATC GGAAGAGCGTCGTGTACG A01587:71 2948804 2948804 TCAGACGTGTGCTCTTCCGATCTGCGAGAGCAA GCGGACCTCATAAAGTGCGTCGTAGTCCGGATT GGAGTCTGCAACTCGACTCCATGAAGTCGGAAT CGCTAGTAATCGTGGATCAGAATGCCACGGTGA ATACGTTCCCGGGCCTTG

REFERENCES

A person of ordinary skill in the biomedical art of can use these patents, patent applications, and scientific references as guidance to predictable results when making and using the invention:

Patent References

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LIST OF EMBODIMENTS

Specific compositions and methods of RNA sequencing to diagnose sepsis have been described. The detailed description in this specification is illustrative and not restrictive or exhaustive. The detailed description is not intended to limit the disclosure to the precise form disclosed. Other equivalents and modifications besides those already described are possible without departing from the inventive concepts described in this specification, as those skilled in the art will recognize. When the specification or claims recite method steps or functions in order, alternative embodiments may perform the tasks in a different order or substantially concurrently. The inventive subject matter is not to be restricted except in the spirit of the disclosure.

When interpreting the disclosure, all terms should be interpreted in the broadest possible manner consistent with the context. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. This invention is not limited to the particular methodology, protocols, reagents, and the like described in this specification and, as such, can vary in practice. The terminology used in this specification is not intended to limit the scope of the invention, which is defined solely by the claims.

All patents and publications cited throughout this specification are expressly incorporated by reference to disclose and describe the materials and methods that might be used with the technologies described in this specification. The publications discussed are provided solely for their disclosure before the filing date. They should not be construed as an admission that the inventors may not antedate such disclosure under prior invention or for any other reason. If there is an apparent discrepancy between a previous patent or publication and the description provided in this specification, the present specification (including any definitions) and claims shall control. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and constitute no admission as to the correctness of the dates or contents of these documents. The dates of publication provided in this specification may differ from the actual publication dates. If there is an apparent discrepancy between a publication date provided in this specification and the actual publication date supplied by the publisher, the actual publication date shall control.

The terms comprise and comprising should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, used, or combined with other elements, components, or steps. The singular terms a, an, and the include plural referents unless context indicates otherwise. Similarly, the word or should cover and unless the context indicates otherwise. The abbreviation e.g., is used to indicate a non-limiting example and is synonymous with the term for example.

When a range of values is provided, each intervening value, to the tenth of the unit of the lower limit, unless the context dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that range of values.

Some embodiments of the technology described can be defined according to the following numbered paragraphs:

1. A method of using unmapped bacterial RNA reads to identify bacteria causing sepsis.

2. A method of using unmapped viral reads to identify sepsis or viral reactivation.

3. A method of using unmapped B/T V(D)J to identify sepsis.

4. A method of using a Principal Component Analysis of RNA splicing entropy to identify sepsis.

5. A method of using RNA lariats to identify sepsis.

6. A method of using a Principal Component Analysis of gene expression, alternative RNA splicing, or alternative transcription start and end to identify sepsis. 

1. A method of treatment of sepsis, comprising the steps of: (a) identifying the sepsis patient to be treated using a diagnostic step, the diagnostic step comprising: (1) obtaining a body sample from the patient; (2) assaying the sample for bacterial RNA reads that identify bacteria causing sepsis; and (3) identifying the bacteria causing sepsis by aligning the RNA reads to a genome of interest; and (b) treating the identified sepsis patient with a treatment for sepsis.
 2. A method of treatment of sepsis, comprising the steps of: (a) identifying the sepsis patient to be treated using a diagnostic step, the diagnostic step comprising: (1) obtaining a body sample from the patient; (2) assaying the sample for viral RNA reads that identify bacteria causing sepsis; and (3) identifying the bacteria causing sepsis by aligning the RNA reads to a genome of interest; and (b) treating the identified sepsis patient with a treatment for sepsis.
 3. A method of treatment of sepsis, comprising the steps of: (a) identifying the sepsis patient to be treated using a diagnostic step, the diagnostic step comprising: (1) obtaining a body sample from the patient; (2) assaying the sample for RNA reads that identify bacteria causing sepsis using a Principal Component Analysis of RNA splicing entropy to identify sepsis; and (3) identifying the bacteria causing sepsis by aligning the RNA reads to a genome of interest; and (b) treating the identified sepsis patient with a treatment for sepsis.
 4. A method of treatment of COVID-19 infection, comprising the steps of: (a) identifying the COVID-19 patient to be treated using a diagnostic step, the diagnostic step comprising: (1) obtaining a body sample from the patient; (2) assaying the sample for RNA reads that identify the patient as having a COVID-19 infection; and (3) identifying the patient as having a COVID-19 infection by aligning the RNA reads to a genome of interest; and (b) treating the identified COVID-19 patient with a treatment for COVID-19 infection.
 5. A method of treatment of acute respiratory distress syndrome (ARDS), comprising the steps of: (a) identifying the ARDS patient to be treated using a diagnostic step, the diagnostic step comprising: (1) obtaining a body sample from the patient; (2) assaying the sample for bacterial RNA reads that identify the patient as having ARDS; and (3) identifying the patient as having ARDS by aligning the RNA reads to a genome of interest; and (b) treating the identified ARDS patient with a treatment for ARDS. 